Our references section is divided
into three parts. Part one consists of abstracts of
three seminal scientific papers published by scientists at UC Berkeley that discuss the molecular biology of DIM in immune
response enhancement. Part two consists of other important papers regarding
DIM and other ingredients in the Berkeley Immune Support Formula. Part three provides a direct search link on Diindolylmethane to the US National Library of Medicine enabling a comprehensive search of all scientific references on Diindolylmethane dating back to 1975. Together they are designed to be a comprehensive
reference source for consumers and healthcare practitiouners investigating the health benefits of
the Berkeley Immune Support Formula and Diindolylmethane.
Important note for readers:
while many of the scientific discoveries and clinical developments listed in
this section are extremely exciting, they are stepping stones in the studies
of Diindolylmethane (DIM) and some of the other key natural ingredients in
the Berkeley Immune Support Formula.
The exploration of clinical applications for Diindolylmethane is an emerging
Only the US FDA has the authority to recognize a compound as a
drug or therapeutic for a particular condition in the US and that only
occurs after the compound has been thoroughly studied and its efficacy
established in four consecutive human clinical trials. At this point in
time, Diindolylmethane and the other natural ingredients in the Berkeley Immune Support Formula are
regarded as dietary supplements and not therapeutics for any specific
condition by the US FDA. The Berkeley Immune Support Formula is a nutritional supplement.
The statements on this website have not been evaluated by the US Food and
Drug Administration. The Berkeley Immune Support Formula is not intended to diagnose, treat, cure or
prevent any disease.
Part I: Scientific References on DIM's Enhancement of the Immune Response
stimulates murine immune function in vitro and in vivo,
Xue L, Pestka J, Maoxiang L, Firestone GL,
Bjeldanes LF, Journal of Nutritional Biochemistry,
published online, 8-20-07. Department of
Nutritional Sciences and Toxicology, University of California, Berkeley,
Diindolylmethane (DIM), a major condensation product of
indole-3-carbinol, exhibits chemopreventive properties in animal models of
cancer. Recent studies have shown that DIM stimulates interferon-gamma (IFN-γ)
production and potentiates the IFN-γ signaling pathway in human breast
cancer cells via a mechanism that includes increased expression of the IFN-γ
receptor. The goal of this study was to test the hypothesis that DIM
modulates the murine immune function. Specifically, the effects of DIM were
evaluated in a panel of murine immune function tests that included
splenocyte proliferation, reactive oxygen species (ROS) generation, cytokine
production and resistance to viral infection. DIM was found to induce
proliferation of splenocytes as well as augment mitogen- and interleukin
(IL)-2-induced splenocyte proliferation. DIM also stimulated the production
of ROS by murine peritoneal macrophage cultures. Oral administration of DIM,
but not intraperitoneal injection, induced elevation of serum cytokines in
mice, including IL-6, granulocyte colony-stimulating factor (G-CSF), IL-12
and IFN-γ. Finally, in a model of enteric virus infection, oral DIM
administration to mice enhanced both clearance of reovirus from the GI tract
and the subsequent mucosal IgA response. Thus, DIM is a potent stimulator of
immune function. This property might contribute to the cancer inhibitory
effects of this indole.
and potentiation of interferon-gamma signaling by 3,3-Diindolylmethane
(DIM) in MCF-7 breast cancer cells.
Xue L, Chatterji U, Bjeldanes EL, Firestone GL, Bjeldanes LF. Department of
Nutritional Sciences and Toxicology, University of California, Berkeley,
94720-3104, USA. Molecular Pharmacology. 2006 Feb;69(2):430-9.
3,3-Diindolylmethane, a natural autolytic product in plants of the
Brassica genus, including broccoli, cauliflower, and Brussels sprouts,
exhibits promising cancer protective activities, especially against mammary
neoplasia in animal models. We observed previously that DIM induced a G(1)
cell-cycle arrest and strong induction of cell-cycle inhibitor p21
expression and promoter activity in both estrogen-responsive and
-independent breast cancer cell lines. We showed recently that DIM
up-regulates the expression of interferon gamma (IFNgamma) in human MCF-7
breast cancer cells. This novel effect may contribute to the anticancer
effects of DIM because IFNgamma plays an important role in preventing the
development of primary and transplanted tumors. In this study, we observed
that DIM activated the IFNgamma signaling pathway in human breast cancer
cells. DIM activated the expression of the IFNgamma receptor (IFNGR1) and
IFNgamma-responsive genes p56- and p69-oligoadenylate synthase (OAS). In
cotreatments with IFNgamma, DIM produced an additive activation of
endogenous p69-OAS and of an OAS-Luc reporter and a synergistic activation
of a GAS-Luc reporter. DIM synergistically augmented the IFNgamma induced
phosphorylation of signal transducer and activator of transcription factor
1, further evidence of DIM activation of the IFNgamma pathway. DIM and IFNgamma produced an additive inhibition of cell proliferation and a
synergistic increase in levels of major histocompatibility complex class-1
(MHC-1) expression, accompanied by increased levels of mRNAs of
MHC-1-associated proteins and transporters. These results reveal novel
immune activating and potentiating activities of DIM in human tumor cells
that may contribute to the established effectiveness of this dietary indole
against various tumor types.
DIM stimulates IFNgamma gene expression in human breast cancer cells via the
specific activation of JNK and p38 pathways.
Xue L, Firestone GL, Bjeldanes LF. Department
of Nutritional Sciences and Toxicology, University of California, 119 Morgan
Hall, Berkeley, CA 94720-3104, USA. Oncogene. 2005 Mar 31;24(14):2343-53.
3,3-Diindolylmethane (DIM) is a promising anticancer agent derived from Brassica vegetables, but the mechanisms of DIM action are largely unknown.
We have shown that DIM can upregulate the expression and stimulate the
secretion of interferon-gamma (IFNgamma) in the human MCF-7 breast cancer
cell line. This novel effect may provide important clues to explain the
anticancer effects of DIM because it is well known that IFNgamma plays an
important role in preventing the development of primary and transplanted
tumors. Utilizing promoter deletions, we show here that the region between
-108 and -36 bp in the IFNgamma promoter, which contains two conserved and
essential regulatory elements, is required for DIM-induced IFNgamma
expression. DIM activates both JNK and p38 pathways, induces the
phosphorylation of c-Jun and ATF-2, and increases the binding of the
homodimer or heterodimer of c-Jun/ATF-2 to the proximal
AP-1.CREB-ATF-binding element. Moreover, studies with specific enzyme
inhibitors showed that up-stream Ca2+-dependent kinase(s) is required for
the inducing effects of DIM in MCF-7 cells. These results establish that
DIM-induced IFNgamma expression in human breast tumor cells is mediated by
activation of both JNK and p38 pathways, which is ultimately dependent on
intracellular calcium signaling.
Part II: Additional Scientific References on DIM and other Ingredients in
Berkeley Immune Support Formula
Oral diindolylmethane (DIM): Pilot evaluation of a
nonsurgical treatment for cervical dysplasia. Gynecological Oncology.
2009 Nov 24. Del Priore G, Gudipudi DK, Montemarano N, Restivo AM,
Malanowska-Stega J, Arslan AA. Indiana University School of Medicine, Dept
of Ob-Gyn, Div Gyn Oncology, Indianapolis, IN, USA; Research Department, New
York Downtown Hospital-member NY-Presbyterian Healthcare, New York, NY, USA.
OBJECTIVE: Standard surgical treatment for CIN may impair fertility
generating a need for alternative treatment options. We tested the efficacy
and toxicity of oral DIM in the treatment of CIN 2 or 3 lesions. METHODS:
Patients with biopsy-proven cervical intraepithelial neoplasia (CIN) 2 or 3
scheduled for loop electrosurgical excision procedure (LEEP) were randomized
2:1 to receive diindolylmethane (DIM) orally at approximately 2 mg/kg/day
for 12 weeks or placebo. Subjects were evaluated every 3-4 months for 1
year. Analysis of data up to 1 year was assessed including Pap smear, HPV,
colposcopy, biopsy and
physical examination were performed at follow-up. Central pathology review
confirmed all histology diagnoses. RESULTS: To date, 64 subjects (mean age
28 years, range 18-61) have been enrolled (45 in the DIM arm, 19 in the
placebo arm), with 60 available for analysis. Average follow-up was 6
months. At enrollment, 58% were diagnosed with CIN 2 and 42% with CIN 3, 57%
of subjects were Caucasian, 15% African American, 12% Hispanic and 17%
Asian. During treatment 2 subjects (3%) complained of nausea (grade 2) at
the 3- to 4-month
visit. No systemic toxicities were observed (normal CBC, LFTs, comprehensive
metabolic). Forty-six subjects had biopsies at first follow-up (77%).
Twenty-one subjects (47%) in the DIM group had improved CIN with a decrease
by 1-2 grades or a normal result. Median time to improvement was 5 months.
Improved Pap smear was
seen in 49% (22/45) with either a less severe abnormality or normal result.
Colposcopy improved in twenty-five subjects in the DIM group (56%). Of these
25 subjects, 21 (84%) had improved colposcopic impression, 13 (52%) had a
decrease in involved quadrants and 18 (72%) had a decrease in lesion number.
Complete colposcopic response was observed in 4 subjects (9%). Stratifying
by level of
dysplasia, age, race, HPV status, tobacco use, contraceptive used did not
alter the results. At median follow-up of 6 months, 85% of subjects have not
required LEEP based on routine clinical triage of improving global
assessment. CONCLUSION: Oral DIM at 2 mg/kg/day is
well tolerated with no significant toxicity. We observed a high rate of
clinically significant improvement in confirmed CIN 2 or 3 lesions among
both treatment groups in this randomized clinical trial.
(DIM) is a novel topoisomerase II alpha catalytic inhibitor
that induces S-phase retardation and mitotic delay in human hepatoma HepG2
2006 Apr;69(4):1320-7. Gong Y, Firestone GL, Bjeldanes LF.Department
of Nutritional Sciences and Toxicology, 119 Morgan Hall, University of
California, Berkeley, CA 94720-3104, USA.
evidence suggests that high consumption of Brassica genus vegetables, such
as broccoli, cabbage, and Brussels sprouts, is very effective in reducing
the risks of several types of cancers. 3,3-Diindolylmethane (DIM), one of
the most abundant and biologically active dietary compounds derived from
Brassica genus vegetables, displays remarkable antitumor activity against
several experimental tumors. In the present study, we demonstrate for the
first time that DIM is a novel catalytic topoisomerase IIalpha inhibitor. In
supercoiled DNA relaxation assay and kinetoplast DNA decatenation assay,
DIM strongly inhibited DNA topoisomerase IIalpha and also partially inhibited
DNA topoisomerases I and IIbeta. DIM did not stabilize DNA cleavage complex
and did not prevent etoposide-induced DNA cleavage complex formation.
Further experiments showed that inhibited topoisomerase
IIalpha-catalyzed ATP hydrolysis, which is a necessary step for the enzyme
turnover. In cultured human hepatoma HepG2 cells, DIM blocked DNA synthesis
and mitosis in a concentration-dependent manner, which was consistent with
the outcome of topoisomerase inhibition in these cell-cycle phases. Our
results identified a new mode of action for this intriguing dietary
component that might be exploited for therapeutic development.
(DIM) and Paclitaxel Act Synergistically to Promote
Apoptosis in HER2/Neu Human Breast Cancer Cells. Journal
of Surgical Research,
2006 May 15;132(2):208-13. K. McGuire, N.
Ngoubilly, M. Neavyn, S. Lanza-Jacoby Department
of Surgery, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107.
breast tumors are difficult to treat. About 25 to 30% of invasive breast
tumors overexpress the HER2/neu oncogene. These tumors are aggressive and
become resistant to chemotherapeutic drugs. Diindolylmethane (DIM), the
active metabolite of indole-3-carbinol, a naturally occurring compound found
in cruciferous vegetables, has been found to have anti-cancer properties in
both humans and animals. DIM has been shown to induce cell cycle arrest and
apoptosis in animal breast cancer models. Because HER2/neu overexpression
confers resistance to paclitaxel, and DIM has anti-tumor effects, we
hypothesized that DIM will enhance the cytotoxic effects of paclitaxel, a
common taxane drug, on human Her2/neu breast cancer cells by potentiating
its effect on cell cycle and stimulating apoptosis. METHODS: The
MDA-MB-435eB1 human Her2/neu breast cancer cells were treated with varying
concentrations of DIM and paclitaxel. The cells were analyzed at different
time points (24, 48, and 72 h). Proliferation was measured by a commercial
cell proliferation assay (Promega Procheck Assay). Cell-cycle analysis and
apoptosis were determined by flow cytometry. Western blot analysis was
performed on to determine the effect of DIM and/or paclitaxel on the
proteins involved in apoptosis, and epidermal growth factor-induced
activation of HER2/neu and ERK1/2 signaling proteins. RESULTS: Both DIM and paclitaxel exhibited time and concentration dependent inhibition of cell
proliferation. TUNEL assay indicated that the combination also increased the
number of apoptotic cells more than either agent alone. The presence of
cleaved poly (ADP-Ribose) polymerase (PARP) significantly increased in the
combination treatment, whereas Bcl-2 is decreased. DIM alone decreased the
activation of the Her2/neu receptor; the combination decreased the
activation of ERK1/ERK2. CONCLUSIONS: DIM in combination with paclitaxel
synergistically inhibits growth of Her2/neu human breast cancer cells
through G2M phase cell-cycle arrest and induction of apoptosis/necrosis. The
Her2/neu receptor and its downstream signaling protein ERK1/2 appear to be
involved in DIM's affect on cell growth and differentiation, whereas
apoptosis appears to be mediated through the mitochondrial pathway
(Bcl-2/PARP). It appears DIM, a naturally occurring, nontoxic compound, may
be a beneficial addition to a traditional (taxane-based) chemotherapy
Inactivation of NF-kappaB by 3,3'-Diindolylmethane (DIM)
contributes to increased apoptosis induced by chemotherapeutic agent in
breast cancer cells. Molecular Cancer Therapeutics,
Rahman KM, Ali S, Aboukameel A, Sarkar SH, Wang Z, Philip PA, Sakr WA, Raz
A. Department of Pathology, Karmanos Cancer Institute, Wayne State
University School of Medicine, 715 HWCRC, 4100 John R, Detroit, MI 48201,
Constitutive activation of Akt or nuclear factor-kappaB (NF-kappaB)
has been reported to play a role in de novo resistance of cancer cells to
chemotherapeutic agents, which is a major cause of treatment failure in
cancer chemotherapy. Previous studies have shown that 3,3'-diindolylmethane
(DIM), a major in vivo acid-catalyzed condensation product of
indole-3-carbinol, is a potent inducer of apoptosis, inhibitor of tumor
angiogenesis, and inactivator of Akt/NF-kappaB signaling in breast cancer
cells. However, little is known regarding the inactivation of Akt/NF-kappaB
that leads to chemosensitization of breast cancer cells to chemotherapeutic
agents, such as Taxotere. Therefore, we examined whether the inactivation
Akt/NF-kappaB signaling caused by DIM could sensitize breast cancer cells to
chemotherapeutic agents both in vitro and in vivo. MDA-MB-231 cells were
simultaneously treated with 15 to 45 micromol/L DIM and 0.5 to 1.0 nmol/L
Taxotere for 24 to 72 h. Cell growth inhibition assay, apoptosis assay,
electrophoretic mobility shift assay, and Western blotting were done. The
combination treatment of 30 micromol/L DIM with 1.0 nmol/L Taxotere elicited
significantly greater inhibition of cell growth compared with either agent
alone. The combination treatment induced greater apoptosis in MDA-MB-231
cells compared with single agents. Moreover, we found that NF-kappaB
activity was significantly decreased in cells treated with DIM and Taxotere.
We also have tested our hypothesis using transfection studies, followed by
combination treatment with DIM/Taxotere, and found that combination
treatment significantly inhibited cell growth and induced apoptosis in
MDA-MB-231 breast cancer cells mediated by the inactivation of NF-kappaB, a
specific target in vitro and in vivo. These results were also supported by
animal experiments, which clearly showed that DIM sensitized the breast
tumors to Taxotere, which resulted in greater antitumor activity mediated by
the inhibition of Akt and NF-kappaB. Collectively, our results clearly
suggest that inhibition of Akt/NF-kappaB signaling by DIM leads to
chemosensitization of breast cancer cells to Taxotere, which may contribute
to increased growth inhibition and apoptosis in breast cancer cells. The
data obtained from our studies could be a novel breakthrough in cancer
therapeutics by using nontoxic agents, such as DIM, in combination with
other conventional therapeutic agents, such as Taxotere.
Pilot study: effect of
3,3-Diindolylmethane DIM) supplements on urinary hormone metabolites in
postmenopausal women with a history of early-stage breast cancer.
Nutrition and Cancer. 2004;50(2):161-7. Dalessandri KM,
Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF Department of
Molecular and Cell Biology, University of California, Berkeley, 94720-3200,
present in Brassica plants such as cabbage, broccoli, and Brussels sprouts,
have been shown to provide potential protection against hormone-dependent
cancers. 3,3-Diindolylmethane(DIM) is under study as one of the main
protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin
County, California, with a history of early-stage breast cancer, were
screened for interest and eligibility in this pilot study on the effect of
DIM supplements on urinary hormone metabolites. The treatment group received
daily DIM (108 mg DIM/day) supplements for 30 days, and the control group
received a placebo capsule daily for 30 days. Urinary metabolite analysis
included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1),
DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol
(6beta-OHC), and cortisol in the first morning urine sample before
intervention and 31 days after intervention. Nineteen women completed the
study,for a total of 10 in the treatment group and 9 in the placebo group.
DIM-treated subjects, relative to placebo, showed a significant increase in
levels of2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to
2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of
estrogen urinary metabolites.
Estrogen metabolism and
risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone
ratio in premenopausal and postmenopausal women. Epidemiology. 2000
Nov;11(6):635-40. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL,
Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Department of Social and Preventive Medicine,
University at Buffalo, State University of New York at Buffalo, Buffalo, NY,
USA, Epidemiology Division of the National Cancer Institute (Istituto
Nazionale Tumori), Milan, Italy, Department of Pediatric Hematology and
Oncology, Medical School of Hannover, Hannover, Germany.
Experimental and clinical evidence suggests that 16alpha-hydroxylated
estrogen metabolites, biologically strong estrogens, are associated with
breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic
activity, are weakly related to this disease. This study analyzes the
association of breast cancer risk with estrogen metabolism, expressed as the
ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested
case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years)
were recruited to a prospective study on breast cancer in Italy, the
"Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women
with a history of cancer and women on hormone therapy were excluded at
baseline. At recruitment, overnight urine was collected from all
participants and stored at -80 degrees C. After an average of 5.5 years of
follow-up, 144 breast cancer cases and four matched controls for each case
were identified among the participants of the cohort. Among premenopausal
women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at
baseline was associated with a reduced risk of breast cancer: women in the
highest quintile of the ratio had an adjusted odds ratio (OR) for breast
cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding
adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results
of this prospective study support the hypothesis that the estrogen
metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is
associated with a reduced risk of invasive breast cancer risk in
3,3-Diindolylmethane DIM) is a strong androgen antagonist in human prostate
Journal of Biological Chemistry. 2003
June 6;278(23);21136-45. Le HT, Schaldach CM, Firestone GL, Bjeldanes LF.
Department of Nutritional Sciences and Toxicology, University of California,
Berkeley, California 94720-3104, USA.
3,3-Diindolylmethane (DIM) is a major digestive product of
indole-3-carbinol, a potential anticancer component of cruciferous
vegetables. Our results indicate that DIM exhibits potent antiproliferative
and antiandrogenic properties in androgen-dependent human prostate cancer
cells. DIM suppresses cell proliferation of LNCaP cells and inhibits
dihydrotestosterone (DHT) stimulation of DNA synthesis. These activities
were not produced in androgen-independent PC-3 cells. Moreover, DIM
inhibited endogenous PSA transcription and reduced intracellular and
secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM
inhibited, in a concentration-dependent manner, the DHT-induced expression
of a prostate-specific antigen promoter-regulated reporter gene construct in
transiently transfected LNCaP cells. Similar effects of DIM were observed in
PC-3 cells only when these cells were co-transfected with a wild-type
androgen receptor expression plasmid. Using fluorescence imaging with green
fluorescent protein androgen receptor and Western blot analysis, we
demonstrated that DIM inhibited androgen-induced androgen receptor (AR)
translocation into the nucleus. Results of receptor binding assays indicated
further that DIM is a strong competitive inhibitor of DHT binding to the AR.
Results of structural modeling studies showed that DIM is remarkably similar
in conformational geometry and surface charge distribution to an established
synthetic AR antagonist, although the atomic compositions of the two
substances are quite different. To our knowledge, DIM is the first
example of a pure androgen receptor antagonist from plants.
Prospective Study of Fruit and Vegetable Intake and Risk
of Prostate Cancer. Journal of the National Cancer Institute.
2007 Jul 24; (Epub ahead of print) Krish VA,
Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB. Affiliations for authors: Research Unit, Division of
Preventive Oncology, Cancer Care Ontario, Toronto, ON, Canada (VAK);
Department of Epidemiology and Public Health, Yale University School of
Medicine, New Haven, CT (VAK, STM); Public Health Sciences Division, Fred
Hutchinson Cancer Research Center, Seattle, WA (UP); Department of
Epidemiology, University of Washington, Seattle, WA (UP); Divisions of
Cancer Epidemiology and Genetics (NC, RBH) and Cancer Control and Population
Sciences (AFS), National Cancer Institute, National Institutes of Health,
Department of Health and Human Services, Bethesda, MD; Josephine Ford Cancer
Center, Henry Ford Health System, Detroit, MI (CCJ).
epidemiologic studies have reported associations between fruit and vegetable
intake and reduced risk of prostate cancer, but the findings are inconsistent
and data on clinically relevant advanced prostate cancer are limited. Methods We
evaluated the association between prostate cancer risk and intake of fruits and
vegetables in 1338 patients with prostate cancer among 29361 men (average
follow-up = 4.2 years) in the screening arm of the Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial. Participants completed both a general risk
factor and a 137-item food-frequency questionnaire at baseline. Cox proportional
hazards models were used to estimate relative risks (RRs) and 95% confidence
intervals (CIs). All statistical tests were two-sided. Results Vegetable and
fruit consumption was not related to prostate cancer risk overall; however, risk
of extraprostatic prostate cancer (stage III or IV tumors) decreased with
increasing vegetable intake (RR = 0.41, 95% CI = 0.22 to 0.74, for high versus
low intake; P(trend) = .01). This association was mainly explained by intake of
cruciferous vegetables (RR = 0.60, 95% CI = 0.36 to 0.98, for high versus low
intake; P(trend) = .02), in particular, broccoli (RR = 0.55, 95% CI = 0.34 to
0.89, for >1 serving per week versus <1 serving per month; P(trend) = .02) and
cauliflower (RR = 0.48, 95% CI = 0.25 to 0.89 for >1 serving per week versus <1
serving per month; P(trend) = .03). We found some evidence that risk of
aggressive prostate cancer decreased with increasing spinach consumption, but
the findings were not consistently statistically significant when restricted to
extraprostatic disease. Conclusion: high intake of cruciferous vegetables,
including broccoli and cauliflower, may be associated with reduced risk of
aggressive prostate cancer, particularly extraprostatic disease.
A phase I
dose-escalation study of oral DIM (3,3'-Diindolylmethane) in
castrate-resistant, non-metastatic prostate cancer.
Transl Res. 2010 Jul 23;2(4):402-11. Heath EI, Heilbrun LK, Li J, Vaishampayan
U, Harper F, Pemberton P, Sarkar FH. Karmanos Cancer Institute, Wayne State
University Detroit, MI, USA.
3'-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen
which down-regulates the androgen receptor and prostate specific antigen (PSA). We
conducted a dose-escalation, phase I study of DIM with objectives to
determine the maximum tolerated dose (MTD), toxicity profile, and
phar-macokinetics (PK) of DIM, and to assess its effects on serum PSA and quality
of life (QoL).PATIENTS AND METHODS: Cohorts of 3-6 patients received
escalating doses of twice daily oral DIM providing DIM at 75 mg, then 150 mg, 225 mg,
and 300 mg. Toxicity was evaluated monthly. Serum PSA and QoL were measured at
baseline, monthly during treatment, and at end of study. RESULTS: 12
patients with castrate-resistant, non-metastatic, PSA relapse prostate cancer
were treated over 4 dose cohorts; 2 patients (at 150 mg and 225 mg, respectively)
underwent intra-patient dose escalation, by one dose level. After oral
administration of the first dose of DIM, the plasma exposure to DIM appeared dose
proportional at doses ranging from 75 to 300 mg, with the mean C(max) and mean
AUC(last) increasing from 41.6 to 236.4 ng/ml and from 192.0 to 899.0 ng/ml*h,
respectively. Continued relatively stable systemic exposure to DIM was achieved
following twice daily oral administration of DIM. Minimal toxicity was
observed. Two of the four patients treated at 300 mg had grade 3 asymptomatic
hyponatremia (AH) discovered on routine blood work. The other 2 patients at this
dose had no AH. Therefore, the maximum tolerated dose (MTD) was deemed to be 300
mg and the recommended phase II dose (RP2D) of DIM was 225 mg twice daily. One
patient without AH at 225 mg experienced a 50% PSA decline. One patient with DIM
dose of 225 mg had PSA stabilization. The other 10 patients had an initial
deceleration of their PSA rise (decrease in slope), but eventually progressed based
on continual PSA rise or evidence of metastatic disease. Ten patients
completed monthly QoL reports for a mean of 6 months (range: 1-13). QoL measures
emotional functioning may have held up somewhat better over time than their physical
was well tolerated. Increasing systemic exposure to DIM was achieved with the
increase of DIM dose. Modest efficacy was demonstrated. Patients' QoL
varied over time with length of treatment. Phase II studies are recommended at
the dose of 225 mg orally twice daily. Diindolylmethane (DIM)
induces a G(1) cell cycle arrest in human breast cancer cells that is
accompanied by Sp1-mediated activation of p21(WAF1/CIP1) expression.
Aug;23(8):1297-305. Hong C, Kim HA, Firestone GL, Bjeldanes LF. Department
of Nutritional Sciences and Toxicology, University of California, Berkeley,
CA 94720, USA.
3,3-Diindolylmethane (DIM) is a promising cancer chemopreventive agent
derived from Brassica food plants. To determine whether this natural indole
has a direct growth inhibitory effect on human breast cancer cells, we
examined the cell cycle regulatory effects of DIM in estrogen-dependent
(MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cell
lines. Results of flow cytometry studies showed that DIM treatment produced
a marked increase (from 51 to 79%) in the proportion of cells in the G(1)
phase of the cell cycle, regardless of estrogen-receptor status. Analyses of
G(1)-acting cell cycle components indicated that the enzymatic activity of
cyclin-dependent kinase (CDK) 2 was also strongly reduced. Western blot
analyses showed that, concurrent with the DIM-induced cell cycle arrest, DIM
stimulated a rapid and pronounced increase in levels of the CDK inhibitor,
p21(WAF1/CIP1) (p21). Northern blot analysis demonstrated that DIM increased
p21 mRNA expression with a maximal 6-7-fold induction, and exposure to
cycloheximide did not block the response. Similar increases in expression of
p21 protein and mRNA were observed in both MCF-7 and MDA-MB-231 human breast
cancer cells, suggesting that DIM induction of p21 expression is independent
of estrogen-receptor signaling and p53. Transient transfection of
5'-deletion constructs of the p21 promoter demonstrated that the first 291
bp segment of the proximal promoter, which contains six promoter specific
transcription factor 1 (Sp1) elements, maintained DIM responsiveness.
Consistent with a role for Sp1 in this response, a reporter construct driven
by three consensus Sp1 binding sites was responsive to DIM. In addition, electrophoretic mobility shift assays showed that DIM induced the binding of
Sp1 and Sp3 to the consensus Sp1 responsive element. Thus, our observations
have uncovered an antiproliferative pathway for DIM that implicates
Sp1/Sp3-induced expression of p21 as a target for cell cycle control in
human breast cancer cells.
Advances in Food and Nutrition Research 2006;51:99-164. Rao
AV, Ray MR, Rao LG, Department of Nutritional Sciences, Faculty of
Medicine, University of Toronto, Toronto, Ontario, Canada.
is now recognized as an important etiological factor in the causation of
several chronic diseases including cancer, cardiovascular diseases,
osteoporosis, and diabetes. Antioxidants play an important role in
mitigating the damaging effects of oxidative stress on cells. Lycopene, a
carotenoid antioxidant, has received considerable scientific interest in
recent years. Epidemiological, tissue culture, and animal studies provide
convincing evidence supporting the role of lycopene in the prevention of
lycopene and vitamin E treatment suppresses the growth of PC-346C human
prostate cancer cells in nude mice. The Journal of Nutrition.
2006 May;136(5):1287-93. Limpens J, Shroder FH, de Ridder
CM, Bolder CA, Wildhagen MF, Obermuller-Jevic UC, Kramer K., Van Weerden WM. Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
studies have repeatedly associated a high intake of lycopene and vitamin E
with reduced prostate cancer risk. The present study examined the ability of
the 2 compounds to reduce tumor growth and prostate-specific antigen (PSA)
plasma levels in the PC-346C orthotopic mouse model of human prostate
cancer. Three days after intraprostatic tumor injection, NMRI nu/nu mice
were administered a daily oral dose of synthetic lycopene [5 or 50 mg/kg
body weight (BW)], vitamin E in the form of alpha-tocopheryl acetate (5 or
50 mg/kg BW), a mixture of lycopene and vitamin E (5 mg/kg BW each), or
vehicle. Intraprostatic tumor volume and plasma PSA concentrations were
measured at regular intervals. Mice were killed when the tumor load exceeded
1000 mm(3) or on d 95 when the study was terminated. Prostate and liver were
analyzed by HPLC for lycopene isomers and alpha- and gamma, delta-tocopherol
concentrations. None of the single treatments significantly reduced tumor
volume. In contrast, combined treatment with lycopene and vitamin E, at 5
mg/kg BW each, suppressed orthotopic growth of PC-346C prostate tumors by
73% at d 42 (P < 0.05) and increased median survival time by 40% from 47 to
66 d (P = 0.02). The PSA index (PSA:tumor volume ratio) did not differ
between experimental groups, indicating that PSA levels were not selectively
affected. Lycopene was detected only in mice supplemented with lycopene. As
in humans, most tissue lycopene was in the cis-isomer conformation, whereas
77% trans-lycopene was used in the dosing material. Liver alpha-tocopherol
concentrations were increased in mice supplemented with both 50 mg/kg (226%,
P < 0.05) and 5 mg/kg vitamin E (41%, P < 0.05), whereas prostate
alpha-tocopherol concentrations were increased only by the higher dose (83%,
P < 0.05). Our data provide evidence that lycopene combined with vitamin E
may inhibit the growth of prostate cancer and that PSA can serve as a
biomarker of tumor response for this treatment regimen.
lycopene and its role in human health and chronic diseases.
CMAJ 2000 Sep 19;163(6):739-44 Agarwal S., Rao AV.,
Department of Nutritional Sciences, Faculty of Medicine, University of
Lycopene is a
carotenoid that is present in tomatoes, processed tomato products and other
fruits. It is one of the most potent antioxidants among dietary carotenoids.
Dietary intake of tomatoes and tomato products containing lycopene has been
shown to be associated with a decreased risk of chronic diseases, such as
cancer and cardiovascular disease. Serum and tissue lycopene levels have
been found to be inversely related to the incidence of several types of
cancer, including breast cancer and prostate cancer. Although the
antioxidant properties of lycopene are thought to be primarily responsible
for its beneficial effects, evidence is accumulating to suggest that other
mechanisms may also be involved. In this article we outline the possible
mechanisms of action of lycopene and review the current understanding of its
role in human health and disease prevention.
Combinations of Tomato and Broccoli Enhance Antitumor Activity in Dunning
R3327-H Prostate Adenocarcinomas. Canene-Adams K, Lindshield B, Wang S,
Jeffery E, Clinton S, Erdman J.,
Cancer Res 2007; 67: (2). January 15, 2007
The consumption of diets containing 5 to 10
servings of fruits and vegetables daily is the foundation of public health
recommendations for cancer prevention, yet this concept has not been tested
in experimental models of prostate cancer. We evaluated combinations of
tomato and broccoli in the Dunning R3327-H prostate adenocarcinoma model.
Male Copenhagen rats (n=206) were fed diets containing 10% tomato, 10%
broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10%
broccoli (10:10 combination) powders for approximately 22 weeks starting 1
month prior to receiving s.c. tumor implants. We compared the effects of
diet to surgical castration (2 weeks before termination) or finasteride (5
mg/kg body weight orally, 6 d/wk). Castration reduced prostate weights,
tumor areas, and tumor weight (62%, P<0.001), whereas finasteride reduced
prostate weights (P<0.0001), but had no effect on tumor area or weight.
Tomato reduced tumor weight by 34% (P<0.05). Broccoli decreased tumor
weights by 42% (P<0.01) whereas the 10:10 combination caused a 52% decrease
(P<0.001). Tumor growth reductions were associated with reduced
proliferation and increased apoptosis, as quantified by proliferating cell
nuclear antigen immunohistochemistry and the ApopTag assay. The combination
of tomato and broccoli was more effective at slowing tumor growth than
either tomato or broccoli alone and supports the public health
recommendations to increase the intake of a variety of plant components.
Selenium inhibition of survivin expression by preventing
Sp1 binding to its promoter. Chun JY, Hu Y, Pinder E, Wu J, Li F, Gao
AC, Molecular Cancer Therapeutics.
2007 Sep;6(9):2572-80. Department of Medicine,
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263,
Survivin, an antiapoptotic protein highly expressed in
cancer, regulates multiple cellular network associated with cancer cell
viability and drug resistance. Inhibition of survivin expression has been
pursued as a valid cancer therapeutic target. In this study, we showed that
selenium, an effective chemopreventive agent for many types of cancers,
down-regulated survivin expression. Selenium inhibited survivin expression
in both mRNA and protein levels in a dose- and time-dependent manner. Using
a series of survivin promoter-luciferase constructs, a 37-bp DNA element in
the survivin core promoter region that mediates the ability of selenium to
inhibit survivin transcription was identified. Gel mobility shift assays and
chromatin immunoprecipitation analyses revealed that selenium prevents the
binding of Sp1 or Sp1-like proteins to the 37-bp cis-acting DNA element in
the survivin promoter. Furthermore, inhibition of survivin expression by
small interfering RNA enhanced selenium's inhibitory effects on cell growth,
whereas overexpression of survivin in LNCaP human prostate cancer cells
desensitized cancer cells to selenium effect, suggesting that the expression
of survivin plays an important role in determining the response of cancer
cells to selenium. Taken together, these results suggest that selenium
down-regulated survivin expression by preventing the binding of Sp1 or
Sp1-like proteins to the promoter of survivin, which contributes at least in
part to the inhibitory effect of selenium on survivin gene transcription. In
addition, down-regulation of survivin expression may account for one of the
molecular mechanisms of the anticancer effects of selenium.
High selenium reduces NF-kappaB-regulated gene expression
in uninduced human prostate cancer cells. Christensen MJ, Nartey ET,
Hada AL, Legg RL, Barzee BR, Journal of Nutrition and Cancer,
Department of Nutrition, Dietetics, and Food Science, Brigham
Young University, Provo, UT 84602, USA.
Nuclear factor kappa B (NF-kappaB) induces expression of
antiapoptotic and pro-inflammatory genes and is constitutively activated in
prostate cancer. We tested the hypothesis that a biologically and
physiologically relevant form and concentration of selenium (Se) may alter
NF-kappa B activation in early prostate cancer cells in the absence of
exogenously added inducers of the NF-kappaB pathway. LNCaP cells were
cultured in medium without added tumor necrosis factor alpha or
lipopolysaccharide but with methylseleninic acid added to provide final
concentrations of Se of 30 nM-7.6 microM. Compared to 50 nM Se, treatment
with 7.6 microM Se virtually eliminated NF-kappaB binding to its DNA
response element and reduced transcription rates and mRNA levels by half for
NF-kappaB-regulated genes. There were no differences due to Se in tyrosine
phosphorylation, inhibitor of kappa B alpha (I kappa B alpha) levels, or NF-kappaB
translocation from cytosol to nucleus. The observation in these basal,
unstimulated cells of altered NF-kappaB binding to DNA in the absence of
effects on the NF-kappaB activation pathway suggests an interaction of Se
with the NF-kappaB protein or an effect on recruitment of NF-kappaB
coactivators or corepressors. Inhibition of transcription factor binding and
anti-apoptotic gene expression may be one mechanism for the chemopreventive
effects of Se against prostate cancer.
Selenium as an anticancer nutrient: roles in cell
proliferation and tumor cell invasion. Zeng H, Combs GF Jr.,
2007 Jun 22, Journal of Nutritional
Biochemistry. United States Department of
Agriculture, Agricultural Research Service, Grand Forks Human Nutrition
Research Center, P.O. Box 9034, Grand Forks, ND 58202-9034, USA.
Selenium is an essential dietary component for animals
including humans, and there is increasing evidence for the efficacy of
certain forms of selenium as cancer-chemopreventive compounds. In addition,
selenium appears to have a protective effect at various stages of
carcinogenesis including both the early and later stages of cancer
progression. Mechanisms for selenium-anticancer action are not fully
understood; however, several have been proposed: antioxidant protection,
enhanced carcinogen detoxification, enhanced immune surveillance, modulation
of cell proliferation (cell cycle and apoptosis), inhibition of tumor cell
invasion and inhibition of angiogenesis. Research has shown that the
effectiveness of selenium compounds as chemopreventive agents in vivo
correlates with their abilities to affect the regulation of the cell cycle,
to stimulate apoptosis and to inhibit tumor cell migration and invasion in
vitro. This article reviews the status of knowledge concerning selenium
metabolism and its anticancer effects with particular reference to the
modulation of cell proliferation and the inhibition of tumor cell invasion.
of DNA repair response in human fibroblasts. Oncogene
(2002) 21, 3663-3669. Seo Y, Sweeney C, and Smith M. Indiana University Cancer Center, Department
of Microbiology, Walther Oncology Center, Indiana University School of
Medicine and Walther Cancer Institute, Indianapolis, IN 46202, USA.
Department of Medicine, Section of Hematology/Oncology, Indiana University
School of Medicine, Indianapolis, IN 46202, USA.
Selenium compounds have a long history
in chemoprevention of mammary and colon cancers in rodent models. Selenium
compounds are in current clinical trials, having shown promise in prevention
of prostate and other human cancers. In human tissues, it has been estimated
that each cell sustains approximately 10 000 potentially mutagenic (if not
repaired) lesions per day due to endogenous DNA damage. Almost no studies
have addressed the potential for selenium compounds to induce DNA repair, a
potential mechanism for their cancer-preventive actions. We show that
selenium in the form of selenomethionine induces a DNA repair response in
normal human fibroblasts in vitro, and protects cells from DNA
damage. We show a possible mechanism for the inducible DNA repair response,
in which enhanced repair complex formation was observed in selenomethionine-treated
selenium and total carotenoids predict mortality among older women living in
the community. Journal of Nutrition. 2006
Jan;136(1):172-6. Ray AL, Semba RD, Walston J., Ferrucci L, Cappola AR,
Ricks MO, Xue QL, Fried LP. The Johns Hopkins Medical Institutions,
Baltimore, MD, USA.
Selenium and the
carotenoids play an important role in antioxidant defenses and in the redox
regulation involved in inflammation. We tested the hypothesis that low
selenium and carotenoids predict mortality in older women living in the
community. Women who were enrolled in the Women's Health and Aging Studies I
and II in Baltimore, MD (n = 632; 70-79 y old) had serum selenium and
carotenoids measured at baseline and were followed for mortality over 60 mo.
Median (minimum, maximum) serum selenium and carotenoids were 1.53 (0.73,
2.51) micromol/L and 1.67 (0.13, 9.10) micromol/L; 14.1% of the women died.
The 5 major causes of death were heart disease (32.6%), cancer (18.0%),
stroke (9.0%), infection (6.7%), and chronic obstructive pulmonary disease
(5.6%). Adjusting for age, education, smoking, BMI, poor appetite, and
chronic diseases, higher serum selenium [hazard ratio (HR) 0.71, 95% CI
0.56-0.90/1 SD increase in log(e) selenium; P = 0.005] and higher serum
total carotenoids (HR 0.77, 95% CI 0.64-0.84/1 SD increase in log(e) total
carotenoids; P = 0.009) were associated with a lower risk of mortality.
Women living in the community who have higher serum selenium and carotenoids
are at a lower risk of death.
antioxidants to regulators in cellular signaling and gene regulation:
Sulforaphane and selenium, partners in adaptive response and prevention of
Free Radical Research. 2006
Aug;40(8):775-87. Brigelius-Flohe R., Banning A. German Institute of
Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114 - 116,
D-14558, Nuthetal, Germany.
of decreased cancer risk with intake of cruciferous vegetables and selenium
is stronger than that reported for fruits and vegetables in general. An
active constituent in cruciferae is sulforaphane. Chemopreventive effects of
both, sulforaphane and selenium have been attributed to an antioxidant
action which certainly is too simplicistic. Sulforaphane induces via
activation of the Nrf2/Keap1 system phase 2 enzymes that protect against
carcinogens and oxidants. Induced enzymes comprise the selenoproteins
thioredoxin reductase-1 (TrxR1) and gastrointestinal glutathione peroxidase
(GI-GPx, GPx2), which contain antioxidant response elements (ARE) in their
promoter regions. Translational realisation of the enhanced transcripts
depends on adequate selenium supply, which explains the synergism of Nrf2
activators and selenium. Regarding tumorigenesis the role of TrxR1 is
ambiguous: it is essential for fast tumor cell growth but also diminishes
vascularisation of tumors. The anticarcinogenic role of GI-GPx is evident
from enhanced gastrointestinal tumor formation in gpx2/gpx1 double KO mice.
Synergy between sulforaphane and selenium in the induction of thioredoxin
reductase 1 requires both transcriptional and translational modulation.
Carcinogenesis, 2003 Mar;24(3):497-503. Nutrition Division, Institute of Food Research,
Norwich Research Park, Norwich NR4 7UA, UK.
Zhang J, Svehikova V., Bao Y, Howie AF, Beckett GJ, Williamson G.
Thioredoxin reductases (TrxRs)
catalyse the NADPH-dependent reduction of thioredoxin and play an important
role in multiple cellular events related to carcinogenesis including cell
proliferation, apoptosis and cell signaling. We have used human hepatoma
HepG2 cells to examine the regulation of TrxRs by isothiocyanate (sulforaphane)
and selenium (Se). We show that TrxR1 mRNA, but not TrxR2 mRNA, is induced
up to 4-fold by sulforaphane, and this increase was abolished by actinomycin
D, a transcription inhibitor. Se, in the form of sodium selenite, induced
TrxR1 at the translational level, as shown by an increase in protein
(2.1-fold) and activity (4.8-fold), but not mRNA. In combination,
sulforaphane and Se synergistically induced TrxR1 protein (5.5-fold),
activity (13-fold) and mRNA (6.5-fold). Although Se does not induce TrxR1
mRNA, Se can delay the degradation of sulforaphane-induced TrxR1 mRNA.
Modulation of TrxR1 mRNA by sulforaphane was glutathione and protein kinase
C-dependent, as L-buthionine-S,R-sulfoximine (a specific inhibitor of
glutathione synthesis), and the protein kinase C inhibitor
1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, significantly reduced the
induction. The combination of sulforaphane and Se also efficiently protected
HepG2 cells from paraquat-induced cell death, whereas sulforaphane-only and
Se-only treatments showed very little if any protective effect. These
results demonstrate that synergy can result from a combination of induction
at the levels of transcription and translation.
Selenium in the maintenance and
therapy of HIV-infected patients. Chemical and Biological Intaractions.
Schrauzer GN, Sacher J. University of California, San Diego,
Department of Chemistry and Biochemistry, La Jolla 92093.
Due to its antiviral effects and its
importance for all immunological functions, the administration of selenium
is suggested as a supportive measure in early as well as in advanced stages
of HIV-induced disease. Initial observations on the effects of selenium
supplementation in HIV-infected patients indicate that selenium causes
symptomatic improvements and possibly slows the course of the disease. As
selenium inhibits reverse transcriptase activity in RNA-virus-infected
animals, supplemental selenium could also prevent the replication of HIV and
retard the development of AIDS in newly HIV-infected subjects. An adequate
supply of selenium and of antioxidant vitamins is also proposed as a measure
to reduce the probability of the placental transmission of HIV in pregnancy.
Suppression of human
immunodeficiency virus type 1 viral load with selenium supplementation: a
randomized controlled trial. Archives
of Internal Medicine.
2007 Jan 22;167(2):148-54. Hurwitz BE, Klaus JR, Lllabre MM, Gonzalez A,
Lawrence PJ, Maher KJ, Greenson JM, Baum MK, Shor-Posner G, Skyler JS,
Despite findings that selenium supplementation
may improve immune functioning, definitive evidence of its impact on human
immunodeficiency virus (HIV) disease severity is lacking. METHODS: High
selenium yeast supplementation (200 mug/d) was evaluated in a double-blind,
randomized, placebo-controlled trial. Intention-to-treat analyses assessed
the effect on HIV-1 viral load and CD4 count after 9 months of treatment.
Unless otherwise indicated, values are presented as mean +/- SD. RESULTS: Of
the 450 HIV-1-seropositive men and women who underwent screening, 262
initiated treatment and 174 completed the 9-month follow-up assessment. Mean
adherence to study treatment was good (73.0% +/- 24.7%) with no related
adverse events. The intention-to-treat analyses indicated that the mean
change (Delta) in serum selenium concentration increased significantly in
the selenium-treated group and not the placebo-treated group (Delta = 32.2
+/- 24.5 vs 0.5 +/- 8.8 microg/L; P<.001), and greater levels predicted
decreased HIV-1 viral load (P<.02), which predicted increased CD4 count
(P<.04). Findings remained significant after covarying age, sex, ethnicity,
income, education, current and past cocaine and other drug use, HIV symptom
classification, antiretroviral medication regimen and adherence, time since
HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses
evaluating treatment effectiveness indicated that the nonresponding
selenium-treated subjects whose serum selenium change was less than or equal
to 26.1 microg/L displayed poor treatment adherence (56.8% +/- 29.8%), HIV-1
viral load elevation (Delta = +0.29 +/- 1.1 log(10) units), and decreased
CD4 count (Delta = -25.8 +/- 147.4 cells/microL). In contrast,
selenium-treated subjects whose serum selenium increase was greater than
26.1 microg/L evidenced excellent treatment adherence (86.2% +/- 13.0%), no
change in HIV-1 viral load (Delta = -0.04 +/- 0.7 log(10) units), and an
increase in CD4 count (Delta = +27.9 +/- 150.2 cells/microL). CONCLUSIONS:
Daily selenium supplementation can suppress the progression of HIV-1 viral
burden and provide indirect improvement of CD4 count. The results support
the use of selenium as a simple, inexpensive, and safe adjunct therapy in
HIV spectrum disease.
Study of prediagnostic selenium level in
toenails and the risk of advanced prostate cancer. Yoshizawa K, Willett WC, Morris SJ, et al. J Natl Cancer Inst.
In a recent randomized intervention trial, the
risk of prostate cancer for men receiving a daily supplement of 200 microg
selenium was one third of that for men receiving placebo. By use of a nested
case-control design within a prospective study, i.e., the Health
Professionals Follow-Up Study, we investigated the association between risk
of prostate cancer and prediagnostic level of selenium in toenails, a
measure of long-term selenium intake. METHODS: In 1986, 51,529 male health
professionals aged 40-75 years responded to a mailed questionnaire to form
the prospective study. In 1987, 33,737 cohort members provided toenail
clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were
mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer
were reported. Case and control subjects were matched by age, smoking
status, and month of toenail return. Selenium levels were determined by
neutron activation. All P values are two-sided. RESULTS: The selenium level
in toenails varied substantially among men, with quintile medians ranging
from 0.66 to 1.14 microg/g for control subjects. When matched case-control
data were analyzed, higher selenium levels were associated with a reduced
risk of advanced prostate cancer (odds ratio [OR] for comparison of highest
to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for
trend = .11). After additionally controlling for family history of prostate
cancer, body mass index, calcium intake, lycopene intake, saturated fat
intake, vasectomy, and geographical region, the OR was 0.35 (95% CI =
0.16-0.78; P for trend = .03). CONCLUSIONS: Our results support earlier
findings that higher selenium intakes may reduce the risk of prostate
Supplementation with the carotenoids lutein or zeaxanthin improves human
visual performance. Ophthalmic & Physiological Optics. Kvansakul J,
Rodriguez-Carmona M., Edgar DF, Barker FM, Kapcke W., Schalch W., Barbur JL.
Applied Vision Research Centre, Department of Optometry and Visual Science,
City University, London, UK.
(MP) is found in diurnal primate species when vision spans a range of
ambient illumination and is mediated by cone and rod photoreceptors. The
exact role of MP remains to be determined. In this study we investigate two
new hypotheses for possible MP functions. OBJECTIVE: As MP absorption
coincides partly with that of rhodopsin, MP may reduce rod signal
effectiveness in the mesopic range, thus extend the usefulness of
cone-mediated vision into the mesopic range. Forward light scatter in the
eye can reduce retinal image contrast. If blue light contributes
significantly to intraocular scatter, selective blue light absorption by MP
could reduce the effects of scatter. DESIGN: We investigated 34 subjects
from a carotenoid supplementation trial. The measurements included high
mesopic contrast acuity thresholds (CATs), macular pigment optical density
(MPOD), wavefront aberrations, and scattered light. The measurements were
made after 6 months of daily supplementation with zeaxanthin (Z), lutein
(L), a combination of the two (C), or placebo (P), and again after a further
6 months of doubled supplementation. RESULTS: The data reveal a trend toward
lower CATs in all groups supplemented, with a statistically significant
improvement in the lutein group (p = 0.001), although there was no
correlation with MPOD. Light scattering in the eye and the root-mean-square
wavefront aberrations show decreasing trends as a result of supplementation,
but no correlation with MPOD. CONCLUSIONS: The results suggest that
supplementation with L or Z increases MPOD at the fovea and at 2.5 degrees ,
and that supplementation can improve CATs at high mesopic levels and hence
visual performance at low illumination.
carotenoids, vitamins A, C, and E, and advanced age-related macular
degeneration. Eye Disease Case-Control Study Group. Journal of the
American Medical Association.1994 Nov 9;272(18):1413-20.
Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD,
Gragoudas ES, Haller J., Miller DT. Epidemiology Unit, Massachusetts
Eye and Ear Infirmary, Boston 02114.
evaluate the relationships between dietary intake of carotenoids and
vitamins A, C, and E and the risk of neovascular age-related macular
degeneration (AMD), the leading cause of irreversible blindness among
adults. DESIGN--The multicenter Eye Disease Case-Control Study.
SETTING--Five ophthalmology centers in the United States. PATIENTS--A total
of 356 case subjects who were diagnosed with the advanced stage of AMD
within 1 year prior to their enrollment, aged 55 to 80 years, and residing
near a participating clinical center. The 520 control subjects were from the
same geographic areas as case subjects, had other ocular diseases, and were
frequency-matched to cases according to age and sex. MAIN OUTCOME
MEASURES--The relative risk for AMD was estimated according to dietary
indicators of antioxidant status, controlling for smoking and other risk
factors, by using multiple logistic-regression analyses. RESULTS--A higher
dietary intake of carotenoids was associated with a lower risk for AMD.
Adjusting for other risk factors for AMD, we found that those in the highest
quintile of carotenoid intake had a 43% lower risk for AMD compared with
those in the lowest quintile (odds ratio, 0.57; 95% confidence interval,
0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein
and zeaxanthin, which are primarily obtained from dark green, leafy
vegetables, were most strongly associated with a reduced risk for AMD (P for
trend = .001). Several food items rich in carotenoids were inversely
associated with AMD. In particular, a higher frequency of intake of spinach
or collard greens was associated with a substantially lower risk for AMD (P
for trend < .001).
Lutein and zeaxanthin in eye and skin health. Clin
Dermatol. 2009 Mar-Apr;27(2):195-201. Roberts RL, Green J, Lewis B.
Kemin Health, LC, 600 E Court Avenue, Suite A, Des Moines, IA 50309-2058,
Less than 20 of the hundreds of carotenoids found in nature are found in the
human body. These carotenoids are present in the body from the foods or
dietary supplements that humans consume. The body does not synthesize them.
Among the carotenoids present in the body, only lutein and its coexistent
isomer, zeaxanthin, are found in that portion of the eye where light is
focused by the lens, namely, the macula lutea. Numerous studies have shown
that lutein and zeaxanthin may provide significant protection against the
potential damage caused by light striking this portion of the retina. In the
eye, lutein and zeaxanthin have been shown to filter high-energy wavelengths
of visible light and act as antioxidants to protect against the formation of
reactive oxygen species and subsequent free radicals. Human studies have
demonstrated that lutein and zeaxanthin are present in the skin, and animal
studies have provided evidence of significant efficacy against light-induced
skin damage, especially the ultraviolet wavelengths. Little was known about
the protective effects of these carotenoids in human skin until recently.
This article reviews the scientific literature pertaining to the effects
that lutein and zeaxanthin exhibit in the human eye and skin.
Vitamin E and immune
response in the aged: molecular mechanisms and clinical implications.
Immonology Reviews. 2005 June;205:269-84. Meydani SN, Han SN, Wu D.
Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at
Tufts University, Boston, MA 02111, USA
Nutritional status has
been indicated as a contributing factor to age-related dysregulation of the
immune response. Vitamin E, a lipid-soluble antioxidant vitamin, is
important for normal function of the immune cells. The elderly are at a
greater risk for vitamin E intake that is lower than recommended levels.
Vitamin E supplementation above currently recommended levels has been shown
to improve immune functions in the aged including delayed-type
hypersensitivity skin response and antibody production in response to
vaccination, which was shown to be mediated through increased production of
interleukin (IL)-2, leading to enhanced proliferation of T cells, and
through reduced production of prostaglandin E(2), a T-cell suppressive
factor, as a result of a decreased peroxynitrite formation. Vitamin E
increased both cell-dividing and IL-producing capacities of naive T cells,
but not memory T cells. The vitamin E-induced enhancement of immune
functions in the aged was associated with significant improvement in
resistance to influenza infection in aged mice and a reduced risk of
acquiring upper respiratory infections in nursing home residents.
supplementation reverses the age-associated decrease in effective immune
synapse formation in CD4+ T cells.
Annals of the New York Academy of Sciences. 2004 December; 1031:412-4. Ahmed
T, Marko M, Wu D, Chung H, Huber B, Meydani SN.
Nutritional Immunology Laboratory, Jean Mayer U.S. Department of Agriculture
Human Nutrition Research Center on Aging at Tufts University, 711 Washington
Street, Boston, MA 02111, USA.
Aging is associated with
impairment of T cell function. We demonstrate here that age-associated
declines in T cell signaling are due to the inability to form effective
immune synapses at the site of the T cell receptor and antigen interaction.
On the basis of our previous research with vitamin E (VE), we hypothesized
that VE supplementation of old CD4(+) T cells enhances effective immune
synapse formation through increased translocation of signaling proteins.
Using confocal microscopy, we found that when exposed to antigen-presenting
cells, CD4(+) T cells from old mice have a lower percentage of effective
immune synapses compared to those from young mice. Furthermore, we show that
in vitro and in vivo VE supplementation increases the percentage of old
CD4(+) T cells capable of forming a functional immune synapse.
action on the immune response. Journal of Nutrition.2004
Jan;134(1):257S-261S. Chew BP, Park JS. Washington State University,
Pullman, WA 99164-6351, USA.
demonstrating the ability of dietary carotenes to prevent infections have
left open the possibility that the action of these carotenoids may be
through their prior conversion to vitamin A. Subsequent studies to
demonstrate the specific action of dietary carotenoids have used carotenoids
without provitamin A activity such as lutein, canthaxanthin, lycopene and
astaxanthin. In fact, these nonprovitamin A carotenoids were as active, and
at times more active, than beta-carotene in enhancing cell-mediated and
humoral immune response in animals and humans. Another approach to study the
possible specific role of dietary carotenoids has used animals that are
inefficient converters of carotenoids to vitamin A, for example the domestic
cat. Results have similarly shown immuno-enhancement by nonprovitamin A
carotenoids, based either on the relative activity or on the type of immune
response affected compared to beta-carotene. Certain carotenoids, acting as
antioxidants, can potentially reduce the toxic effects of reactive oxygen
species (ROS). These ROS, and therefore carotenoids, have been implicated in
the etiology of diseases such as cancer, cardiovascular and
neurodegenerative diseases and aging. Recent studies on the role of
carotenoids in gene regulation, apoptosis and angiogenesis have advanced our
knowledge on the possible mechanism by which carotenoids regulate immune
function and cancer.
Relationship between plasma carotenoids and prostate cancer. Nutritional Cancer.
2005;53(2):127-34. Hursting SD. Department of
Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston,
TX 77030, USA
Carotenoids, particularly lycopene, are thought to
decrease prostate cancer risk, but the relationship between plasma carotenoid
concentrations and risk in various populations has not been well characterized.
Comparing 118 non-Hispanic Caucasian men mainly from southeast Texas with
nonmetastatic prostate cancer with 52 healthy men from the same area, we
conducted a case-control analysis evaluating associations between risk and
plasma levels of total carotenoids, beta-cryptoxanthin, alpha- and
trans-beta-carotene, lutein and zeaxanthin, total lycopenes, trans-lycopene,
total cis-lycopenes, and cis-lycopene isoforms 1, 2, 3, and 5. Risk for men with
high plasma levels of alpha-carotene, trans-beta-carotene, beta-cryptoxanthin,
and lutein and zeaxanthin was less than half that for those with lower levels.
In contrast, we observed no significant associations for total lycopenes,
all-trans-lycopene, and cis-lycopene isomer peaks 2, 3, and 5, although high
levels of cis-lycopene isomer peak 1 were inversely associated with risk.
Analysis of men with aggressive disease (Gleason scores of > or =7, n = 88) vs.
less aggressive cases (Gleason scores of <7, n = 30) failed to reveal
significant associations between carotenoid levels and the risk of diagnosis
with aggressive disease. These findings suggest that, in these men, higher
circulating levels of alpha-cryptoxanthin, alpha-carotene, trans-beta-carotene,
and lutein and zeaxanthin may contribute to lower prostate cancer risk but not
to disease progression.
inhibits extracellular, intracellular, and antibiotic-resistant strains of
Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors.
2002 May 28;99(11):7610-5. Proclamation of the National
Academy of Sciences. Fahey JW, Haristoy X, Dolan PM, Kensler TW,
Sholtus I, Stephenson KK, Talalay P, Lozniewski A. Lewis B. and Dorothy
Cullman Cancer Chemoprotection Center, Department of Pharmacology and
Molecular Sciences, The Johns Hopkins University School of Medicine, 725
North Wolfe Street, Baltimore, MD 21205-2185, USA.
with Helicobacter pylori is a cosmopolitan problem, and is especially common
in developing regions where there is also a high prevalence of gastric
cancer. These infections are known to cause gastritis and peptic ulcers, and
dramatically enhance the risk of gastric cancer. Eradication of this
organism is an important medical goal that is complicated by the development
of resistance to conventional antimicrobial agents and by the persistence of
a low level reservoir of H. pylori within gastric epithelial cells.
Moreover, economic and practical problems preclude widespread and intensive
use of antibiotics in most developing regions. We have found that
sulforaphane [(-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an
isothiocyanate abundant as its glucosinolate precursor in certain varieties
of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3
reference strains and 45 clinical isolates of H. pylori [minimal inhibitory
concentration (MIC) for 90% of the strains is <or=4 microg/ml], irrespective
of their resistance to conventional antibiotics. Further, brief exposure to
sulforaphane was bactericidal, and eliminated intracellular H. pylori from a
human epithelial cell line (HEp-2). In complementary experiments,
sulforaphane blocked benzo[a]pyrene-evoked forestomach tumors in ICR mice.
This protection resulted from induction of phase 2 detoxication and
antioxidant enzymes, and was abrogated in mice lacking the nrf2 gene, which
regulates phase 2 enzymes. Thus, the dual actions of sulforaphane in
inhibiting Helicobacter infections and blocking gastric tumor formation
offer hope that these mechanisms might function synergistically to provide
diet-based protection against gastric cancer in humans.
Broccoli sprouts: an
exceptionally rich source of inducers of enzymes that protect against
Proclamations of the National Academy of Sciences. 1997 Sep
16;94(19):10367-72. Fahey JW, Zhang Y, Talalay P. Brassica
Chemoprotection Laboratory and Department of Pharmacology and Molecular
Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD
phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide
hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a
powerful strategy for achieving protection against carcinogenesis,
mutagenesis, and other forms of toxicity of electrophiles and reactive forms
of oxygen. Since consumption of large quantities of fruit and vegetables is
associated with a striking reduction in the risk of developing a variety of
malignancies, it is of interest that a number of edible plants contain
substantial quantities of compounds that regulate mammalian enzymes of
xenobiotic metabolism. Thus, edible plants belonging to the family
Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain
substantial quantities of isothiocyanates (mostly in the form of their
glucosinolate precursors) some of which (e.g., sulforaphane or
4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2
enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers
including broccoli and cauliflower contain 10-100 times higher levels of
glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding
mature plants. Glucosinolates and isothiocyanates can be efficiently
extracted from plants, without hydrolysis of glucosinolates by myrosinase,
by homogenization in a mixture of equal volumes of dimethyl sulfoxide,
dimethylformamide, and acetonitrile at -50 degrees C. Extracts of 3-day-old
broccoli sprouts (containing either glucoraphanin or sulforaphane as the
principal enzyme inducer) were highly effective in reducing the incidence,
multiplicity, and rate of development of mammary tumors in
Impact of Nrf2 on UVB-induced skin inflammation/photoprotection
and photoprotective effect of sulforaphane. Mol Carcinog. 2010 Dec 28. Saw
CL, Huang MT, Liu Y, Khor TO, Conney AH, Kong AN. Center for Cancer
Prevention Research, Rutgers, The State University of New Jersey,
Piscataway, New Jersey.
Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin,
inflammation, and drive skin carcinogenesis. Previously, we have shown that
sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via
factor (erythroid-derived 2)-like 2 (Nrf2) and others have shown that
sprout extracts containing high SFN protected against UV-induced skin
carcinogenesis in SKH-1 hairless mice. A recent study showed that there was
difference between Nrf2 knockout (Nrf2 KO) and Nrf2 wild-type (WT) BALB/C
after exposing to high dose of UVB. Since Nrf2 plays critical roles in the
anti-oxidative stress/anti-inflammatory responses, it is relevant to assess
role of Nrf2 for photoprotection against UV. In this context, the role of
UVB-induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was
single dose of UVB (300 mJ/cm(2)) resulted in skin inflammation in both WT
Nrf2 KO (-/-) mice (KO mice) at 8 h and 8 d following UVB irradiation. In
mice inflammation returned to the basal level to a greater extent when
to the KO mice. SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the
of sunburn cells back to their basal level by 8 d after UVB irradiation.
Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β
interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells
the KO mice were significantly higher as compared to that in the WT. Taken
together, our results show that functional Nrf2 confers a protective effect
against UVB-induced inflammation, sunburn reaction, and SFN-mediated
photoprotective effects in the skin.
Dose-dependent modulation of the T cell proteome by ascorbic acid.
British Journal of Nutrition.
2007 Jan;97(1):19-26. Grant MM, Mistry N,
Lunec J, Griffiths HR. Aston University,
To investigate the hypothesis that the micronutrient ascorbic
acid can modulate the functional genome, T cells (CCRF-HSB2) were treated with
ascorbic acid (up to 150 microM) for up to 24 h. Protein expression changes were
assessed by two-dimensional electrophoresis. Forty-one protein spots which
showed greater than two-fold expression changes were subject to identification
by matrix-assisted laser desorption ionisation time of flight MS. The confirmed
protein identifications were clustered into five groups; proteins were
associated with signalling, carbohydrate metabolism, apoptosis, transcription
and immune function. The increased expression of phosphatidylinositol transfer
protein (promotes intracellular signalling) within 5 min of ascorbic acid
treatment was confirmed by Western blotting. Together, these observations
suggest that ascorbic acid modulates the T cell proteome in a time- and
dose-dependent manner and identify molecular targets for study following
antioxidant supplementation in vivo.
Smoking-induced monocyte dysfunction is reversed by vitamin C supplementation
in vivo. Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):120-6. Epub 2006 Oct 19 Stadler N, Eggermann J, Voo S, Kranz A, Waltenberger J. Department of Cardiology, University of Maastricht,
Cardiovascular Research Institute of Maastricht, P. Debyelaan 25, NL-6202 AZ
Maastricht, The Netherlands.
OBJECTIVE: The role of antioxidants in preventing vascular
disease remains controversial. Vascular endothelial growth factor (VEGF-A) is
important for endothelial and monocyte function. This study investigated the
negative effects of smoking on monocyte migratory responsiveness to VEGF-A and
the usefulness of vitamin C to prevent smoking-induced monocyte dysfunction.
METHODS AND RESULTS: The chemotactic response of isolated monocytes from a
cohort of 17 non-smokers and 10 smokers toward VEGF-A was assessed. VEGF-A
significantly stimulated the migration of monocytes in non-smokers; the
monocytes from smokers failed to respond to VEGF-A. Repeated analysis after 2
weeks of vitamin C intake (2 g/d) showed a fully restored VEGF-A-induced
monocyte migration in smokers. VEGF-A serum levels were not altered by vitamin
C. VEGF-A-inducible kinase activity was intact in monocytes from smokers as
assessed by in vitro kinase assay. Monocyte dysfunction can be mimicked in vitro
by challenging monocytes with a range of reactive oxygen species (ROS).
CONCLUSIONS: Stimulation of monocyte migration by VEGF-A was severely attenuated
in smokers, and the deficit observed was surmounted by vitamin C
supplementation. The negative effects of smoking on monocyte function may
translate into adverse impacts on VEGF-A-dependent repair processes such as
arteriogenesis. These results propose a causative role of oxidative stress in
smoking-induced monocyte dysfunction.
Vitamin C deficiency increases the lung pathology of
influenza virus-infected gulo-/- mice. Journal Nutrition.
2006 Oct;136(10):2611-6. Li W, Maeda N, Beck MA.
This study was designed to determine the effects of vitamin C
deficiency on the immune response to infection with influenza virus. l-Gulono-gamma-lactone
oxidase gene-inactivated mice (gulo-/- mice) require vitamin C supplementation
for survival. Five-wk-old male and female gulo-/- mice were provided water or
water containing 1.67 mmol/L vitamin C for 3 wk before inoculation with
influenza A/Bangkok/1/79. There were no differences in lung influenza virus
titers between vitamin C-adequate and -deficient mice; however, lung pathology
in the vitamin C-deficient mice was greater at 1 and 3 d after infection but
less at d 7 compared with vitamin C-adequate mice. Male vitamin C-deficient mice
had higher expression of mRNA for regulated upon activation normal T expressed
and secreted (RANTES), IL-1beta, and TNF-alpha in the lungs at d 1 after
infection compared with male controls. However, at d 3 after infection, male
vitamin C-deficient mice had less expression of mRNA for RANTES, monocyte
chemotactic protein-1 (MCP-1), and IL-12 compared with male controls. None of
these differences were observed in female mice. Vitamin C-deficient male mice
also had greater nuclear factor-kappaB activation as early as 1 d after
infection compared with male controls. These data suggest that vitamin C is
required for an adequate immune response in limiting lung pathology after
influenza virus infection.
Effect of Vitamin C on common cold: randomized controlled trial. European
Journal of Clinical Nutrition. 2006
Jan;60(1):9-17. Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S.
Epidemiology and Prevention Division, Research
Center for Cancer Prevention and Screening, National Cancer Center, Chuo-ku,
OBJECTIVE: To investigate the relationship between the common
cold and vitamin C supplementation. DESIGN: A double-blind, 5-year randomized
controlled trial. SETTING: A village in Akita prefecture, one of the regions in
Japan with the highest mortality from gastric cancer. SUBJECTS: Participants in
annual screening programs for circulatory diseases conducted under the National
Health and Welfare Services Law for the Aged, and diagnosed as having atrophic
gastritis. Of the 439 eligible subjects, 144 and 161 were assigned to receive 50
or 500 mg of vitamin C, respectively, after protocol amendment. During the
supplementation phase, 61 dropped out, and 244 completed the trial.
Intervention: Daily vitamin C supplementation of 50 mg (low-dose group) or 500
mg (high-dose group). RESULTS: Total number of common colds (per 1000
person-months) was 21.3 and 17.1 for the low- and high-dose groups,
respectively. After adjustment for several factors, the relative risks (95%
confidence interval (CI)) of suffering from a common cold three or more times
during the survey period was 0.34 (0.12-0.97) for the high-dose group. No
apparent reduction was seen for the severity and duration of the common cold.
CONCLUSION: A randomized, controlled 5-year trial suggests that vitamin C
supplementation significantly reduces the frequency of the common cold but had
no apparent effect on the duration or severity of the common cold.
Dietary vitamin D and calcium and risk of colorectal
cancer: a 19-year prospective study in men. Lancet 1985;1:307-9. Garland C, Shekelle R B,
Barrett-Connor E, Criqui MH, Rossof A H and Paul O.
Mortality rates from colon cancer in the USA are highest in
populations exposed to the least amounts of natural sunlight; differences in
endogenous vitamin D production and calcium absorption could be responsible. To
investigate this possibility, the association of dietary vitamin D and calcium
with 19-year risk of colorectal cancer was examined in 1954 men who had
completed detailed, 28-day dietary histories in the period 1957-59. Risk of
colorectal cancer was inversely correlated with dietary vitamin D and calcium.
In the quartiles of a combined index of dietary vitamin D and calcium, from
lowest to highest, observed risks of colorectal cancer were 38.9, 24.5, 22.5,
and 14.3/1000 population. This association remained significant after adjustment
for age, daily cigarette consumption, body mass index, ethanol consumption, and
percentage of calories obtained from fat.
Vitamin D: its role in cancer prevention and treatment. Prog Biophys Mol Bio.
2006 Sep;92(1):49-59. Epub 2006 Mar 10.
University Medical Center, 715 Albany Street, M-1013, Boston, MA 02118, USA.
Vitamin D, the sunshine vitamin, has been recognized for almost
100 years as being essential for bone health. Vitamin D provides an adequate
amount of calcium and phosphorus for the normal development and mineralization
of a healthy skeleton. Vitamin D made in the skin or ingested in the diet,
however, is biologically inactive and requires obligate hydroxylations first in
the liver to 25-hydroxyvitamin D, and then in the kidney to
1,25-dihydroxyvitamin D. 25-Hydroxyvitamin D is the major circulating form of
vitamin D that is the best indicator of vitamin D status. 1,25-dihydroxyvitamin
D is the biologically active form of vitamin D. This lipid-soluble hormone
interacts with its specific nuclear receptor in the intestine and bone to
regulate calcium metabolism. It is now recognized that the vitamin D receptor is
also present in most tissues and cells in the body. 1,25-dihydroxyvitamin D, by
interacting with its receptor in non-calcemic tissues, is able to elicit a wide
variety of biologic responses. 1,25-dihydroxyvitamin D regulates cellular growth
and influences the modulation of the immune system. There is compelling
epidemiologic observations that suggest that living at higher latitudes is
associated with increased risk of many common deadly cancers. Both prospective
and retrospective studies help support the concept that it is vitamin D
deficiency that is the driving force for increased risk of common cancers in
people living at higher latitudes. Most tissues and cells not only have a
vitamin D receptor, but also have the ability to make 1,25-dihydroxyvitamin D.
It has been suggested that increasing vitamin D intake or sun exposure increases
circulating concentrations of 25-hydroxyvitamin D, which in turn, is metabolized
to 1,25-dihydroxyvitamin D(3) in prostate, colon, breast, etc. The local
cellular production of 1,25-dihydroxyvitamin D acts in an autocrine fashion to
regulate cell growth and decrease the risk of the cells becoming malignant.
Therefore, measurement of 25-hydroxyvitamin D is important not only to monitor
vitamin D status for bone health, but also for cancer prevention.
Vitamin D in defense of the human immune response. Ann NY Acad Sci.
2007 Nov;1117:94-105. Epub 2007 Jul.
Adams JS, Liu PT, Chun R, Modlin RL, Hewison M.
of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute,
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room B-131, Los Angeles, CA
Defensin is a generic name reserved for an endogenously
synthesized antimicrobial agent. The purpose of this review is to describe a
series of discoveries that led to the proposal that 25-hydroxylated metabolites
of vitamin D are key, intracellular regulators of the synthesis and action of
naturally occurring defensin molecules against bacterial antigens. The
discussion will (1) highlight the basic elements of human immune response that
is responsive to vitamin D, (2) recount work relevant to the extrarenal
expression of the vitamin D-1-hydroxlase (CYP27b1) in the macrophage as an
initiator of the innate immune response, and (3) describe recent work on the
relevance of the vitamin D intracrine-autocrine-paracrine system in a model of a
common and devastating human disease, tuberculosis.
Vitamin D compounds: activity against microbes and cancer.
Anticancer research 2006
Jul-Aug;26(4A):2531-42. Gombart AF, Luong QT,
Koeffler HP. Division of Hematology / Oncology, Cedars-Sinai Medical Center,
Burns and Allen Research Institute, David Geffen School of Medicine at UCLA,
8700 Beverly Blvd., Los Angeles, CA 90048, USA
Vitamin D3 is produced in skin and is sequentially metabolized by
the liver and kidney to the biologically active form 1,25-dihydroxyvitamin D3
[1,25(OH)2D3]. It is a seco-steroid hormone that regulates calcium homeostasis
within the body. The genomic actions of 1,25(OH)2D3 are modulated through the
vitamin D receptor (VDR). VDR belongs to a superfamily of nuclear receptors that
transduce hormonal signals from the immediate environment and transactivate
genes in response to these signals. Target genes contain hormone response
elements (VDREs) in their promoters to which heterodimers of VDR and retinoid X
receptors (RXR) can bind and transactivate expression of the target genes. The
VDR is expressed in at least 30 different target tissues including bone, kidney,
blood, breast, prostate, gut, activated B- and T- lymphocytes, monocytes and
keratinocytes). Most dividing cell types, normal and malignant, can express VDR
and respond to 1,25(OH)2D3. Although 1,25(OH)2D3 and its analogs (termed
deltanoids) are important regulators of calcium and bone metabolism, their non-calciotropic
activities that include inhibition of cell proliferation, promotion of cell
differentiation and modulation of immune cell function have spurred interest in
therapeutic applications in a wide variety of diseases. In this report, the
anticancer and newly discovered antimicrobial actions of 1,25(OH)2D3 and
deltanoids are reviewed.
Vitamin D and Calcium supplementation reduces cancer risk: results of a
randomized trial. American Journal of Clinical Nutrition. 2007 Jun:85(6):
1586-91. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.
Osteoporosis Research Center, Creighton University, Omaha, NE
BACKGROUND: Numerous observational studies have found
supplemental calcium and vitamin D to be associated with reduced risk of common
cancers. However, interventional studies to test this effect are lacking.
OBJECTIVE: The purpose of this analysis was to determine the efficacy of calcium
alone and calcium plus vitamin D in reducing incident cancer risk of all types.
DESIGN: This was a 4-y, population-based, double-blind, randomized
placebo-controlled trial. The primary outcome was fracture incidence, and the
principal secondary outcome was cancer incidence. The subjects were 1179
community-dwelling women randomly selected from the population of healthy
postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at
latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg
supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU
vitamin D3/d (Ca + D), or placebo. RESULTS: When analyzed by intention to treat,
cancer incidence was lower in the Ca + D women than in the placebo control
subjects (P < 0.03). With the use of logistic regression, the unadjusted
relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were
0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined
to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to
0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the
Ca-only group. In multiple logistic regression models, both treatment and serum
25-hydroxyvitamin D concentrations were significant, independent predictors of
cancer risk. CONCLUSIONS: Improving calcium and vitamin D nutritional status
substantially reduces all-cancer risk in postmenopausal women. This trial was
registered at clinicaltrials.gov as NCT00352170.
A Single Dose of Vitamin D Enhances Immunity to Mycobacteria.
Am. J. Respir. Crit. Care Med., Volume 176, Number 2, July
Rationale: Vitamin D was used to treat tuberculosis in the
pre-antibiotic era. Prospective studies to evaluate the effect of vitamin D
supplementation on antimycobacterial immunity have not previously been
performed. Objectives: To determine the effect of vitamin D supplementation
on antimycobacterial immunity and vitamin D status. Methods: A double-blind
randomized controlled trial was conducted in 192 healthy adult tuberculosis
contacts in London, UK. Participants were randomized to receive a single
oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.
Measurements and Main Results: The primary outcome measure was assessed with
a functional whole blood assay (BCG-lux assay) that measures the ability of
whole blood to restrict luminescence, and thus growth, of recombinant
reporter mycobacteria in vitro; the read-out is expressed as a luminescence
ratio (luminescence post-infection/baseline luminescence). Interferon-gamma
responses to the M. tuberculosis antigens early secretory antigenic target-6
and culture filtrate protein 10 were determined with a second whole blood
assay. Vitamin D supplementation significantly enhanced the ability of
participants' whole blood to restrict BCG-lux luminescence in vitro compared
to placebo (mean luminescence ratio at follow-up 0.57 vs. 0.71 respectively,
95% CI for difference 0.01 to 0.25; P=0.03) but did not affect
antigen-stimulated Interferon-gamma secretion. Conclusions: A single oral
dose of 2.5 mg vitamin D significantly enhanced the ability of participants'
whole blood to restrict BCG-lux luminescence in vitro without affecting
antigen-stimulated Interferon-gamma responses. Clinical trials should be
performed to determine whether vitamin D supplementation prevents
reactivation of latent tuberculosis infection.
Toll-like receptor triggering of a vitamin D-mediated human
antimicrobial response. Science.
2006 Mar 24;311(5768):1770-3. Epub 2006 Feb. Liu
PT, Stenger S, Li H. Department of Microbiology,
Immunology, and Molecular Genetics, University of California at Los Angeles, Los
Angeles, CA 90095, USA
In innate immune responses, activation of Toll-like receptors (TLRs)
triggers direct antimicrobial activity against intracellular bacteria, which in
murine, but not human, monocytes and macrophages is mediated principally by
nitric oxide. We report here that TLR activation of human macrophages
up-regulated expression of the vitamin D receptor and the vitamin
D-1-hydroxylase genes, leading to induction of the antimicrobial peptide
cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also
observed that sera from African-American individuals, known to have increased
susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient
in supporting cathelicidin messenger RNA induction. These data support a link
between TLRs and vitamin D-mediated innate immunity and suggest that differences
in ability of human populations to produce vitamin D may contribute to
susceptibility to microbial infection.
Human cathelicidin antimicrobial peptide (CAMP) gene
is a direct target of the vitamin D receptor and is strongly up-regulated in
myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005
Jul;19(9):1067-77. Gombart AF, Borregaard N, Koeffler HP. Department of
Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, David
Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA
The innate immune system of mammals provides a rapid response to
repel assaults from numerous infectious agents including bacteria, viruses,
fungi, and parasites. A major component of this system is a diverse combination
of cationic antimicrobial peptides that include the alpha- and beta-defensins
and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and
three of its analogs induced expression of the human cathelicidin antimicrobial
peptide (CAMP) gene. This induction was observed in acute myeloid leukemia
(AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal
human bone marrow (BM) -derived macrophages and fresh BM cells from two normal
individuals and one AML patient. The induction occurred via a consensus vitamin
D response element (VDRE) in the CAMP promoter that was bound by the vitamin D
receptor (VDR). Induction of CAMP in murine cells was not observed and
expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to
wild-type levels. Comparison of mammalian genomes revealed evolutionary
conservation of the VDRE in a short interspersed nuclear element or SINE in the
CAMP promoter of primates that was absent in the mouse, rat, and canine genomes.
Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in
regulation of primate innate immunity.
Vitamin D3, gamma interferon, and control of proliferation
of Mycobacterium tuberculosis by human monocytes. Immunology 1986
Jan;57(1):159-63. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J,
Previous studies have shown that recombinant interferon gamma (IFN-gamma),
crude T cell supernatants, or appropriate T-cell lines can cause total
inhibition of the growth of M. tuberculosis inside murine peritoneal
macrophages. In similar experiments with human monocytes much smaller effects
are seen. This could be due to the relative immaturity of these cells. Because
dihydroxy vitamin D3 (1,25-(OH)2 D3) can cause phenotypic differentiation of
immature leukemic lines into macrophage-like cells, we have explored the
possibility that exposure to cholecalciferol metabolites in vitro might increase
the ability of monocytes to control proliferation of M. tuberculosis, or cause
monocytes to mature into cells able to respond appropriately to IFN-gamma.
Incubation of monocytes with three cholecalciferol metabolites induced
anti-tuberculosis activity to an extent that correlated with their binding
affinities to the intracellular receptor protein for the derivatives. 1,25-(OH)2
D3 also primed monocytes for phorbol myristate acetate-triggered reduction of
nitroblue tetrazolium. The effects were additive rather than synergistic with
those of IFN-gamma. Monocytes incubated with IFN-gamma developed 25-OH D3
1-hydroxylase activity, detected by conversion of tritiated 25-(OH) D3 to a more
polar metabolite which coeluted with 1,25-(OH)2 D3 on straight and reverse-phase
HPLC. The latter is a more active form in vivo. These findings help to explain
claims for the efficacy of vitamin D in the treatment of some forms of
tuberculosis, and also the occasional finding of raised serum calcium, and
disturbed vitamin D metabolism in these patients.
Evidence that vitamin D3 increases serum
25-hydroxyvitamin D more efficiently than does vitamin D2. Trang HM et al. 1998. Am J Clin Nutr 68:854-858.
Department of Laboratory Medicine, University of Toronto,
and The Wellesley Hospital, Canada.
In all species tested, except humans, biological differences
between vitamins D2 and D3 are accepted as fact. To test the presumption of
equivalence in humans, we compared the ability of equal molar quantities of
vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [25(OH)D], the measure of
vitamin D nutrition. Subjects took 260 nmol (approximately 4000 IU) vitamin D2
(n=17) or vitamin D3 (n=55) daily for 14 d. 25(OH)D was assayed with a method
that detects both the vitamin D2 and D3 forms. With vitamin D3, mean (+/-SD)
serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L
after treatment. With vitamin D2, the 25(OH)D concentration went from
43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after. The increase in 25(OH)D
with vitamin D3 was 23.3+/-15.7 nmol/L, or 1.7 times the increase obtained with
vitamin D2 (13.7+/-11.4 nmol/L; P=0.03). There was an inverse relation between
the increase in 25(OH)D and the initial 25(OH)D concentration. The lowest 2
tertiles for basal 25(OH)D showed larger increases in 25(OH)D: 30.6 and 25.5
nmol/L, respectively, for the first and second tertiles. In the highest tertile
[25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for
comparison with each lower tertile). Although the 1.7-times greater efficacy for
vitamin D3 shown here may seem small, it is more than what others have shown for
25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The
assumption that vitamins D2 and D3 have equal nutritional value is probably
wrong and should be reconsidered.
Recombinant human interferon gamma in the treatment of
rheumatoid arthritis: double blind placebo controlled study. Ann.
Machold KP, Neumann K, Smolen.
Rheum Dis.1992 Sep;51(9):1039-43.
Interferon gamma (IFN gamma) has been advocated in open studies
as a beneficial remission inducing drug for the treatment of rheumatoid
arthritis (RA). The work reported here was designed to assess the therapeutic
potential of IFN gamma in the treatment of RA in a double blind placebo
controlled study. It was found that patients treated with IFN gamma improved
significantly with respect to morning stiffness, grip strength, swelling of an
index joint, and erythrocyte sedimentation rate. Furthermore significantly more
responders (according to predetermined response criteria) were found in the
group treated with IFN gamma. Only minor adverse effects and no significant
toxicity with respect to clinical or laboratory parameters were observed.
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