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Simultaneously Blocking Glycolysis and Fat Metabolism Can the use of DCA and a fatty acid metabolism blocker together force more cancer cells into using aerobic metabolism? Tim McGough used green tea extract, which contains EGCG, in his fantastic response. DCA works by reactivating mitochondria and shifts metabolism from glycolysis to glucose oxidation. Hopefully the cancer cell will then undergo apoptosis. However, cancer cells have an alternate energy source: fat metabolism. This page explores to possibility of blocking fat metabolism to help force the cell into apoptosis. Oral squamous cell carcinoma is a cancer that does not respond well to DCA. This study, Head and Neck Cancer Cell Lines Are Resistant to Mitochondrial-Depolarization-Induced Apoptosis states: "Results: ΔΨm in head and neck cell lines started to show slight loss of ΔΨm, while HL-60 showed significant loss of ΔΨm after 30 min of treatment. All cell lines demonstrated complete mitochondrial depolarization within 24 h, however, only the control cell line HL-60 underwent apoptosis. In addition, HNSCC cell lines did not demonstrate cytoplasmic cytochrome c release despite significant mitochondrial membrane depolarization, while HL-60 cell initiated apoptosis and cytochcrome c release after 24 h of treatment. Conclusions: Head and neck cancer cell lines exhibit defects in mitochondrial-membrane-depolarization-induced apoptosis as well as impaired release of cytochrome c despite significant mitochondrial membrane depolarization. Proximal defects in the mitochondrial apoptosis pathway are a feature of HNSCC.(head and neck squamous cell carcinoma)" Note that although the cell lines were depolarized, apoptosis did not occur. So I checked to see if fatty acid metabolism is used by squamous cell carcinoma.

Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mantena SK, Sharma SD, Katiyar SK. Mol Cancer Ther. 2006 Feb;5(2):296-308. PMID: 16505103 doi: 10.1158/1535-7163.MCT-05-0448 The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy. The evaluation of ancient herbal medicines may indicate novel strategies for the treatment of prostate cancer, which remains the leading cause of cancer-related deaths in American men (1). In our present investigation, we show that a naturally occurring isoquinoline alkaloid, berberine, significantly inhibits the proliferation and reduces the viability of DU145 and PC-3 as well as LNCaP cells (Fig. 1), which suggests that berberine may be an effective chemotherapeutic agent against both androgen-sensitive and androgen-insensitive prostate cancer cells. Importantly, we found that berberine did not exhibit toxicity to nonneoplastic human prostate epithelial cells under the conditions used, except for a moderate reduction in cell viability at higher concentrations when cells were treated in vitro for an extended period of time. In conclusion, the results of the present study indicate that berberine inhibits proliferation and induces G1-phase arrest and apoptosis in human prostate cancer cells but not in normal human prostate epithelial cells. In addition, we provide mechanistic evidence that berberine-induced apoptosis in prostate carcinoma cells, particularly hormone-refractory prostate carcinoma cells, is mediated through enhanced expression of Bax, disruption of the mitochondrial membrane potential, and activation of caspase-3.

It was concluded that omega-3 fatty acid could inhibit the proliferation of pancreatic cancer cell line SW1990 cells and promote their apoptosis. The down-regulation of the cyclin E expression by omega-3 fatty acid might be one of the mechanisms for its anti-tumor effect on pancreatic cancer. Modulatory effects of EPA and DHA on proliferation and apoptosis of pancreatic cancer cells. Zhang W, Long Y, Zhang J, Wang C. J Huazhong Univ Sci Technolog Med Sci. 2007 Oct;27(5):547-50. PMID: 18060632

Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase. Jiang F, Bao J, Li P, Nicosia SV, Bai W. J Biol Chem. 2004 Dec 17;279(51):53213-21. Epub 2004 Oct 12. PMID: 15485861 doi: 10.1074/jbc.M410395200 Overall, the study suggests that the down-regulation of telomerase activity by 1,25(OH)2VD3 and the resulting cell death are important components of the response of OCa cells to 1,25(OH)2VD3-induced growth suppression. Progressive shortening of telomere associated with cell divisions limits the life span of normal cells and eventually leads to senescence. To become immortal, human cancers including OCa are invariably associated with activation of mechanism that maintains telomere length. Approximately 85-90% of cancers show reactivation of telomerase. The present study shows that telomerase in OCa cells is down-regulated by 1,25(OH)2VD3. Down-regulation of telomerase is due to decreased stability of hTERT mRNA rather than VDRE-mediated transcriptional repression through the putative VDRE present in the regulatory region of the hTERT gene. It is known that the inhibition of telomerase may lead to a phenotypic lag during which cells would continue to divide until the point at which the telomeres became critically short. This phenomenon may explain why the apoptotic induction by 1,25(OH)2VD3 needs the treatment for more than 6 days. As mentioned in the results, no detectable shortening of telomeric repeats was observed in parental OVCAR3 cells after 9 days of treatment with 1,25(OH)2VD3 (Fig. 4D). This is likely due to the fact that the short telomere (about 3 kb) in OVCAR3 cells is very close to the minimal length required for survival and that cells with detectably shorter telomere may have been selected against apoptosis. It has been shown that transformed human cells enter crisis once the terminal restriction fragment of the telomere reaches a length of about 4 kb. This is insufficient to protect chro

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.

Lim YC, Lee SH, Song MH, Yamaguchi K, Yoon JH, Choi EC, Baek SJ. Growth inhibition and apoptosis by (-)-epicatechin gallate are mediated by cyclin D1 suppression in head and neck squamous carcinoma cells. Eur J Cancer. 2006 Dec;42(18):3260-6. Epub 2006

The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of beta-catenin levels and alterations in the expression of TCF-beta-catenin target genes. Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A, Monego G, Ranelletti FO, Palozza P. Carcinogenesis. 2007 Jun;28(6):1202-9. Epub 2006 Dec 20. PMID: 17183061 doi:10.1093/carcin/bgl254

Scientists have known that cruciferous vegetables contain a host of chemopreventive agents that act in many different ways to block cancer development.2 Key among these products are indole-3-carbinol (I3C) and sulforaphane.1,3 Cancer cells need a brisk blood supply to support their rampant growth and reproduction. Preliminary studies in vitro and in vivo have found that apigenin inhibits blood vessel growth (angiogenesis) in human ovarian cancer cells, blocking production of two main signaling molecules required to stimulate vessel growth.20,21 Scientists confirmed this effect in ovarian cancer cells, also finding that apigenin strongly inhibits cell proliferation.22 Apigenin and BITC: Complementary Cancer Protection Cancer cells also need energy to support their frenetic reproductive activity. Researchers applied apigenin to human pancreatic cancer cells in culture and studied the cells' uptake of glucose.14 Astonishingly, they found that apigenin deprived energy-hungry cancer cells of glucose to support their voracious appetites and aggressive growth. It did this by down-regulating vital glucose-transporting proteins in cancer cells. This approach could effectively starve deadly cancer cells and stop them in their tracks. Another cruciferous vegetable component receiving rave reviews is the sulfur-containing molecule benzyl isothiocyanate, or BITC (pronounced "bitsy"). As with apigenin, population studies have shown that higher intakes of BITC correlate with reduced risk of cancers of the lung, breast, and colon30 while blocking cancer development in a host of different ways. BITC induces breast cancer cell death by apoptosis (programmed cell death), interfering with cancer cells' energy utilization and causing them to die off before they can contribute to tumor growth.31,32 In human ovarian cancer cells, BITC induces apoptosis by a different mechanism. It stimulates "signaling" molecules that tell cancer cells it's time to close up shop.

Ursolic acid, a natural pentacyclic triterpenoid carboxylic acid, is the major component of some traditional medicine herbs and is well known to possess a wide range of biological functions, such as antioxidative, anti-inflammatory, antihyperlipidemic and anticancer activities, that are able to counteract endogenous and exogenous biological stimuli. Ursolic acid has been noted for their antitumor-promotion activities. Ursolic acid is capable of inducing apoptosis in tumor cells on one side and to prevent malignant transformation of normal cells on the other side. It also interferes with numerous enzymes, including the ones serving directly to DNA synthesis

Vitamin D-induced up-regulation of tumour necrosis factor alpha (TNF-alpha) in prostate cancer cells. Golovko O, Nazarova N, Tuohimaa P. Life Sci. 2005 Jun 17;77(5):562-77. Epub 2005 Feb 25. PMID: 15904673 doi:10.1016/j.lfs.2004.10.072 Combined addition of human recombinant TNF-alpha with calcitriol or CB1093 cause enhanced effect in induction of apoptosis. We conclude that under physiological conditions vitamin D activates only the transcription of TNF-alpha gene, for TNF-alpha protein synthesis additional cofactors are required. Therefore a cooperation of vitamin D and TNF-alpha may play an important role in the control of cell growth in prostate cancer.

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.

Research just published in the American Association for Cancer Research's Cancer Prevention Research identifies a class of flavonoids called anthocyanins in black raspberries that's been shown to inhibit cancer cell growth and stimulate apoptosis (the death of cancer cells) in the esophagus of rats treated with an esophageal carcinogen

Berberine inhibits human tongue squamous carcinoma cancer tumor growth in a murine xenograft model. Ho YT, Yang JS, Lu CC, Chiang JH, Li TC, Lin JJ, Lai KC, Liao CL, Lin JG, Chung JG. Phytomedicine. 2009 Sep;16(9):887-90. Epub 2009 Mar 20. PMID: 19303753 Our primary studies showed that berberine induced apoptosis in human tongue cancer SCC-4 cells in vitro. But there is no report to show berberine inhibited SCC-4 cancer cells in vivo on a murine xenograft animal model. SCC-4 tumor cells were implanted into mice and groups of mice were treated with vehicle, berberine (10mg/kg of body weight) and doxorubicin (4mg/kg of body weight). The tested agents were injected once per four days intraperitoneally (i.p.), with treatment starting 4 weeks prior to cells inoculation. Treatment with 4mg/kg of doxorubicin or with 10mg/kg of berberine resulted in a reduction in tumor incidence. Tumor size in xenograft mice treated with 10mg/kg berberine was significantly smaller than that in the control group. Our findings indicated that berbeirne inhibits tumor growth in a xenograft animal model. Therefore, berberine may represent a tongue cancer preventive agent and can be used in clinic.

Vitamin D and breast cancer. Bertone-Johnson ER. Ann Epidemiol. 2009 Jul;19(7):462-7. Epub 2009 Feb 20. Review. PMID: 19230714 Though the relationship between vitamin D and breast cancer remains unclear, a growing body of evidence suggests that vitamin D may modestly reduce risk. A large number of in vitro studies indicate that vitamin D can inhibit cell proliferation and promote apoptosis and cell differentiation in breast tumor tissue. Results from analytic studies of sunlight exposure and dietary intake have been inconsistent but together generally support a modestly protective role of vitamin D, at least in some population subgroups. Studies using blood vitamin D metabolites to assess vitamin D status may be less prone to misclassification than those of diet and sunlight exposure. Overall, the two prospective and four case-control studies of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D tend to support a protective effect in older women. The relationship between common vitamin D receptor polymorphisms and risk remains unclear. Many questions about this relationship clearly remain, including the utility of assessing vitamin D through diet and sunlight exposure, the relationship between plasma metabolites, and the potential modifying effects of age, menopausal status and tumor characteristics. Given that vitamin D status is modifiable, additional prospective studies are necessary to determine if vitamin D may have important potential for breast cancer prevention.

"Apigenin is described as a nonmutagenic bioflavonoid which is presented in leafy plants and vegetables (e.g., parsley, artichoke, basil, celery) and has significant chemopreventive activity against UV-radiation. Current research trials indicate that it may reduce DNA oxidative damage; inhibit the growth of human leukemia cells and induced these cells to differentiate; inhibit cancer cell signal transduction and induce apoptosis; act as an anti-inflammatory; and as an anti-spasmodic or spasmolytic. "

"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

Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids. Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM, Thomas MJ, Thornburg T, Kulik G, Smith A, Edwards IJ, D'Agostino R, Zhang H, Wu H, Kang JX, Chen YQ. J Clin Invest. 2007 Jul;117(7):1866-75. PMID: 17607361 Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.