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"Worcester, MA - Current research suggests that TNF-receptor associated protein-1 (TRAP-1) may prevent cancer cell death. The related report by Leav et al, "Cytoprotective Mitochondrial Chaperone TRAP-1 as a Novel Molecular Target in Localized and Metastatic Prostate Cancer," appears in the January 2010 issue of the American Journal of Pathology. Prostate cancer cells are often resistant to cell death. Researchers led by Dr. Dario C. altieri of the University of Massachusetts Medical School, therefore, explored the role of TRAP-1, a protein thought to regulate cell death, in prostate cancer survival. TRAP-1 was highly expressed in both high-grade human prostate cancer lesions and mouse models of prostate cancer, but not in benign or normal prostate tissue. In addition, TRAP-1 overexpression in non-cancer prostate cells inhibited cell death, whereas TRAP-1-deficient prostate cancer cells had enhanced levels of cell death. Moreover, treatment with Gamitrinib, which inhibits TRAP-1, resulted in prostate cancer cell death, but not death of non-cancerous prostate cells. Therefore, targeting TRAP-1 via Gamitrinib treatment may be a viable therapeutic strategy for patients with advanced prostate cancer."

"Língzhī (traditional Chinese: 靈芝; simplified Chinese: 灵芝; Japanese: reishi; Korean: yeongji, hangul: 영지) is the name for one form of the mushroom Ganoderma lucidum, and its close relative Ganoderma tsugae. Ganoderma lucidum enjoys special veneration in Asia, where it has been used as a medicinal mushroom in traditional Chinese medicine for more than 4,000 years, making it one of the oldest mushrooms known to have been used in medicine. Lingzhi may possess anti-tumor, immunomodulatory and immunotherapeutic activities, supported by studies on polysaccharides, terpenes, and other bioactive compounds isolated from fruiting bodies and mycelia of this fungus (reviewed by R. R. Paterson[4] and Lindequist et al.[7]). It has also been found to inhibit platelet aggregation, and to lower blood pressure (via inhibition of angiotensin-converting enzyme[8]), cholesterol and blood sugar.[9] Laboratory studies have shown anti-neoplastic effects of fungal extracts or isolated compounds against some types of cancer. In an animal model, Ganoderma has been reported to prevent cancer metastasis,[10] with potency comparable to Lentinan from Shiitake mushrooms.[11] The mechanisms by which G. lucidum may affect cancer are unknown and they may target different stages of cancer development: inhibition of angiogenesis (formation of new, tumor-induced blood vessels, created to supply nutrients to the tumor) mediated by cytokines, cytoxicity, inhibiting migration of the cancer cells and metastasis, and inducing and enhancing apoptosis of tumor cells

Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. Li Y, Liu L, Tollefsbol TO. FASEB J. 2009 Dec 17. [Epub ahead of print] PMID: 20019239 doi: 10.1096/fj.09-149328 Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16(INK4a). Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Michelakis ED, Webster L, Mackey JR. Br J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Review. PMID: 18766181 doi:10.1038/sj.bjc.6604554 The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg-1 day-1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study. Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity res

Soy Food Intake and Breast Cancer Survival. Xiao Ou Shu et al. JAMA Vol. 302 No. 22, December 9, 2009; 302(22):2437-2443. Results During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer-related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor-positive or -negative breast cancer and was present in both users and nonusers of tamoxifen. Conclusion Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.

Vitamin D for cancer prevention: global perspective. Garland CF, Gorham ED, Mohr SB, Garland FC. Ann Epidemiol. 2009 Jul;19(7):468-83. Review. PMID: 19523595

Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocator. Pereira CV, Machado NG, Oliveira PJ. Toxicol Sci. 2008 Oct;105(2):408-17. Epub 2008 Jul 3. PMID: 18599498 doi: 10.1124/jpet.107.128017 The data from the present work appear to show that berberine also presents some degree of toxicity to "nontumor" systems, which should be carefully understood. ANT inhibition in nontumor cells by berberine would be responsible for a decrease in energy production and could also result in MPT induction. To the best of our knowledge, no full toxicity assessment exists for berberine in humans, although its use in several commercially available supplements suggests that the compound may present a relatively wide safety interval. In fact, a study with patients with congestive heart failure treated with 1.2 g/day of oral berberine revealed low toxicity and resulted into an average plasma concentration of 0.11 mg/l which would translate into 0.3µM (Zeng and Zeng, 1999Go). Repeated cumulative treatments, alternative forms of formulation (e.g., topical application vs. injection) or more importantly, active mitochondrial accumulation due to its positive charge would be expected to increase its concentration in cells into the range of concentrations used in this study. Empirical data from nontraditional medicines plus the use of extensive clinical assays would allow the use of berberine as a promising antimelanoma agent while maintaining its safety for humans. In radial/vertical forms of melanoma, a possible topical application of berberine would also be possible, thus minimizing side effects on other organs. In conclusion, the present work identifies the ANT as an important target for berberine, with clear relevance for its proposed antitumor effects.

Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Mantena SK, Sharma SD, Katiyar SK. Carcinogenesis. 2006 Oct;27(10):2018-27. Epub 2006 Apr 18. PMID: 16621886 doi:10.1093/carcin/bgl043 In the present investigation, we show that berberine, which is present abundantly in Berberis plant species, significantly inhibits the viability, proliferation and induces cell death in human epidermoid carcinoma A431 cells (Figure 1), but this effect was not found in normal human epidermal keratinocytes under the identical conditions, except for a non-significant reduction in cell viability at higher concentrations of berberine (50 and 75 µM) and treatment of cells for a longer period of time (72 h). These data suggested that berberine may be examined as an effective chemotherapeutic agent against non-melanoma skin cancers. In conclusion, our study indicates that berberine inhibits growth, induces G1 arrest and apoptotic cell death of human epidermoid carcinoma A431 cells. We also provide mechanistic evidences that berberine-induced apoptosis in human epidermoid carcinoma cells is mediated through disruption of mitochondrial membrane potential and activation of caspase 3 pathway, although other pathways may have a role and that require further investigation. Moreover, further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the prevention of non-melanoma skin cancers.

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. JAMA. 2009 Nov 18;302(19):2119-2126. v PMID: 19920236 Conclusion Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.

"A study conducted by Cedric Garland and other prominent vitamin D researchers determined that women with vitamin D levels above 52 ng/ml have half the risk of developing breast cancer as those with 13 ng/ml! Garland (et al) estimates that 58,000 new cases of breast cancer in the U.S. could be prevented per year by raising vitamin D levels to 52 ng/ml. Imagine what the global impact could be! "

Review article: vitamin D acquisition and breast cancer risk. Pérez-López FR, Chedraui P, Haya J. Reprod Sci. 2009 Jan;16(1):7-19. Review. PMID: 19144887 DOI: 10.1177/1933719108327595 Conclusions: Although there are controversiAl results, it seems plausible that sufficient endogenous vitamin D levels may have a protective function on mammary cells, reducing breast cancer risk.

Association between plasma 25-hydroxyvitamin D and breast cancer risk. Crew KD, Gammon MD, Steck SE, Hershman DL, Cremers S, Dworakowski E, Shane E, Terry MB, Desai M, Teitelbaum SL, Neugut AI, Santella RM. Cancer Prev Res (Phila Pa). 2009 Jun;2(6):598-604. Epub 2009 May 26. PMID: 19470790 In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of >32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is ≥40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.

Vitamin D from dietary intake and sunlight exposure and the risk of hormone-receptor-defined breast cancer. Blackmore KM, Lesosky M, Barnett H, Raboud JM, Vieth R, Knight JA. Am J Epidemiol. 2008 Oct 15;168(8):915-24. Epub 2008 Aug 27. PMID: 18756015 doi:10.1093/aje/kwn198 This study suggests that vitamin D is associated with a reduced risk of breast cancer regardless of ER/PR status of the tumor. Future studies with a larger number of receptor-negative and mixed tumors are required.

The role of vitamin D in cancer prevention. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. Am J Public Health. 2006 Feb;96(2):252-61. Epub 2005 Dec 27. Review. PMID: 16380576 DOI: 10.2105/AJPH.2004.045260 Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.

Dietary vitamin D and cancers of the oral cavity and esophagus. Lipworth L, Rossi M, McLaughlin JK, Negri E, Talamini R, Levi F, Franceschi S, La Vecchia C. Ann Oncol. 2009 Sep;20(9):1576-81. Epub 2009 Jun 1. PMID: 19487490 Conclusion: We observed inverse associations between dietary vitamin D intake and risk of SCCE and, perhaps, oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavy consumers of alcohol.

Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC. J Natl Cancer Inst. 2006 Apr 5;98(7):451-9. PMID: 16595781 doi:10.1093/jnci/djj101 Conclusions: Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.

The role of vitamin D in cancer prevention. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. Am J Public Health. 2006 Feb;96(2):252-61. Epub 2005 Dec 27. Review. PMID: 16380576 DOI: 10.2105/AJPH.2004.045260 Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects

Are sunlight deprivation and influenza epidemics associated with the onset of acute leukemia? Timonen T, Näyhä S, Koskela T, Pukkala E. Haematologica. 2007 Nov;92(11):1553-6. PMID: 18024404 doi:10.3324/haematol.10799 Month of diagnosis of 7,423 cases of acute leukemia (al) in Finland during 1964-2003 were linked with data on influenza and solar radiation. Acute myeloblastic leukemia (AML) showed the highest risk in the dark season. During the light season, the incidence decreased by 58% (95% confidence interval, 16-79%) per 1,000 kJ/m2/d increase of solar radiation. Independent of solar radiation, AML increased by 9% (95% confidence interval, 0-19%) during influenza epidemics. Reoccurring at the same time annually, darkness-related vitamin D deficiency and influenza could cause successive and co-operative mutations leading to al with a short latency.

Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. J Clin Oncol. 2009 Aug 10;27(23):3757-63. Epub 2009 May 18. PMID: 19451439 DOI: 10.1200/JCO.2008.20.0725 Conclusion Vitamin D deficiency may be associated with poor outcomes in breast cancer.

Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Carcinogenesis. 2009 Jul;30(7):1170-80. Epub 2009 Apr 29. Review. PMID: 19403841