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.
Update, 27 January 2010... Researchers find leukemia cells metabolize fat to avoid cell death shows that etomoxir and orlistat target fatty acid oxidation.
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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.
I realized this possibility initially studying the patents of Dr. Karen Newell. Inspired again by recent work of Dr. Zongjian Zhu, I started the search again into this area and discovered an over-the-counter fat metabolism blocker, vanadyl sulfate, that may work. EGCG is another candidate. Here is the line of thought on this topic.
1. The importance of fatty acid metabolism to cancer cells:
2. The Newell patents indicate the combination of a glycolytic and fat metabolism blocker is effective
3. Metformin as an anti-cancer drug
4. Vanadyl Sulfate... An alternative to the prescription drug metformin
5. EGCG is another possible fat metabolism blocker:
6. Using DCA and a fat metabolism blocker in combination:
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The importance of fatty acid metabolism to cancer cells:
Some additional papers relating to this are placed under the EGCG and vanadyl sulfate sections below.
Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by Microarray-Bioinformatics analysis. "The analysis of 10 colorectal cancer tissue specimens demonstrated that genes involved in fatty acid metabolic pathways had high rates of overexpression."
Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer.
".... Recent studies showed that prostate cancer is associated with changes of fatty acid metabolism. Several enzymes involved in the metabolism of fatty acids have been determined to be altered in prostate cancer relative to normal prostate, which is indicative of an enhanced -oxidation pathway in prostate cancer. Increased fatty acid utilization in prostate cancer provides both ATP and acetyl-coenzyme A (CoA); subsequently, increased availability of acetyl-CoA makes acceleration of citrate oxidation possible, which is an important energy source as well. Dominant fatty acid metabolism rather than glycolysis has the potential to be the basis for imaging diagnosis and targeted treatment of prostate cancer."
Fatty acid rather than glucose metabolism is the dominant bioenergetic pathway in prostate cancer 2008.
"1. Prostate tissue is characterized by dominant fatty acid metabolism as its energy source. 2. Malignant prostate cell lines have neither increased fatty acid nor glucose metabolism compared to a benign cell line, consistent with a slow rate of metabolism and growth."
Characterization of a novel metabolic strategy used by drug-resistant tumor cells "We show that drug-resistant cells have low mitochondrial membrane potential, use nonglucose carbon sources (fatty acids) for mitochondrial oxygen consumption when glucose becomes limited," [Maybe DCA resistant cancers switch to fat metabolism too?]
Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cells. "Fatty acid synthase-catalyzed endogenous fatty acid metabolism appears to be an obligatory acquisition selecting a biologically aggressive sub-group of cancer cells capable of growth and survival upon stresses such as hypoxia, low pH and/or nutritional deprivation."
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. It is:
Endogenous fatty acid synthesis in squamous cell carcinomas of the oral cavity "We found that incorporation of14C in the total lipids of squamous cell carcinoma was significantly higher than in the other tissues."
Fatty acid synthase expression in squamous cell carcinoma of the tongue: clinicopathological findings. "The expression of FAS in OSCC of the tongue is associated with the microscopic characteristics that determine disease progression and prognosis."
A pilot study of fatty acid metabolism in oral squamous cell carcinoma. "These results indicate that cerulenin exerts selective cytotoxic effects on squamous carcinoma cells and can induce their apoptosis. These findings suggest that targeting of fatty acid synthesis may be useful in the treatment of squamous cell carcinomas." [cerulenin is a fatty acid
Overexpression of Fatty Acid Synthase in Oesophageal Squamous Cell Dysplasia and Carcinoma
"Our results demonstrate that FAS is expressed in almost all oesophageal carcinomas of both usual and special types and dysplastic lesions, suggesting that FAS may be upregulated continuously from the early stage of oesophageal squamous cell carcinogenesis to established carcinoma."
Effects of Epigallocatechin-3-gallate on Growth, Epidermal Growth Factor Receptor Signaling Pathways, Gene Expression, and Chemosensitivity in Human Head and Neck Squamous Cell Carcinoma Cell Lines shows EGCG works.
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The Newell patents indicate the combination of a glycolytic and fat metabolism blocker is effective:
Both papers report experimental evidence.
"Systems and methods for treating human inflammatory and proliferative diseases and wounds, with fatty acid metabolism inhibitors and/or glycolytic inhibitors"
Systems and methods for treating human inflammatory and proliferative diseases and wounds, with UCP and/or FAS antibody or other inhibitor, optionally with a fatty acid metabolism inhibitor and/or a glucose metabolism inhibitor
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Metformin as an anti-cancer drug
In the paper by Dr. Zhu, the anti-diabetes drug metformin was shown to be effective against cancer. Metformin is a prescription drug and has side effects we'd rather not deal with. However, there are some good research articles on metformin and its anti-cancer activity. Beneath this section are some alternatives to metformin (vanadyl sulfate and EGCG) that do not require prescriptions and appear much safer to use.
Metformin and reduced risk of cancer in diabetic patients
Diabetes Drug Metformin Activates AMPK, Increases Glycolysis, Inhibits Oxidative Phosphorylation and Selectively Reduces Growth of p53-Deficient Tumors in Mice. 2007
Prevention of Pancreatic Cancer Induction in Hamsters by Metformin. Gastroenterology, Volume 120, Issue 5, Pages 1263-1270. "Results: Although 50% of the hamsters in the high-fat group developed malignant lesions, none was found in the HF+Met group (P<0.05). "
Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells
In Breast Cancer Patients With Diabetes Metformin Increases Pathologic Complete Response Rates
Diabetes drug 'may stop cancers' 2005
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Vanadyl Sulfate... An alternative to the prescription drug metformin
Vanadyl sulfate (sometimes called vanadium) is a common supplement available from many firms. It appears to work very similarly to metformin. See, for example: Vanadyl Sulfate Improves Hepatic and Muscle Insulin Sensitivity in Type 2 Diabetes and Effects of Metformin and Vanadium on Leptin Secretion from Cultured Rat Adipocytes
And like metformin, vanadyl sulfate is known to block cancer development.
Dietary vanadyl(IV) sulfate inhibits chemically-induced mammary carcinogenesis.
Vanadium—an element of atypical biological significance "Vanadium is also emerging as a potent anti-carcinogenic agent"
In vitro and in vivo antineoplastic effects of ortrovanadate "In the present study we ]have demonstrated that orthovanadate at concentrations of 5-10 uM is cytotoxic to proliferating cells
including primary cultures and tumour cell lines. However, concentrations of up to 50 uM did not affect the viability of nonproliferating
cells. The cytotoxicity appears to be dependent on the vanadium concentration rather than on the oxidation state
of vanadium or the vanadium compound. Furthermore, tumour cell lines with different proliferative rates were equally sensitive
to orthovanadate cytotoxicity. Although the mechanisms responsible for the cytotoxicity are not known, addition of H202
potentiated orthovanadate cytotoxicity suggesting that hydroxyl or vanadium radicals may be involved. In vivo subcutaneous
injections of orthovanadate into mice containing MDAY-D2 tumours resulted in the inhibition of tumour growth by 85-100%. These data indicated that orthovanadate at concentrations greater than 5 uM has antineoplastic properties and may be useful as a chemotherapeutic agent."
Suppression of cell proliferation, induction of apoptosis and cell cycle arrest: Chemopreventive activity of vanadium in vivo and in vitro 2006. Rajarshi Sankar Ray, Balaram Ghosh, Ajay Rana, Malay Chatterjee. "Vanadium (ammonium monovanadate) at a concentration of 0.5 ppm (4.27 mol/l) was supplemented in drinking water and given ad libitum to the experimental groups for 24 weeks....Results of both the in vivo and in vitro study demonstrate that vanadium has the potential to be developed into an anti-breast cancer drug in the near future. "
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EGCG is another possible fat metabolism blocker:
Fatty acid metabolism in breast cancer cells : differential inhibitory effects of epigallocatechin gallate (EGCG) and C75
"Endogenous fatty acid metabolism is crucial to maintain the cancer cell malignant phenotype. ....... Our results establish EGCG as a potent and specific inhibitor of fatty acid synthesis (FASN), which may hold promise as a target-directed anti-cancer drug.
Fatty acid metabolism in cancer cells: Differential inhibitory effects of epigallocatechin (EGCG) and C75 Similar to above paper.
Green tea catechin inhibits fatty acid synthase without stimulating carnitine palmitoyltransferase-1 or inducing weight loss in experimental animals.
"The enzyme fatty acid synthase (FASN) is highly expressed in many human carcinomas and its inhibition is cytotoxic to human cancer cells. The use of FASN inhibitors has been limited until now by anorexia and weight loss, which is associated with the stimulation of fatty acid oxidation.......CONCLUSION: EGCG is a FASN inhibitor with anticancer activity which does not exhibit cross-activation of fatty acid oxidation and does not induce weight loss, suggesting its potential use as an anticancer drug.
Induction of Cancer Cell Apoptosis by Flavonoids Is Associated with Their Ability to Inhibit Fatty Acid Synthase Activity Again, EGCG is shown to block fatty acid metabolism.
EGCG is found in both black and green teas. This may help explain some of the good responses we have seen in people using both tea and caffeine.
In Tim McGough's story, Lulu reports that "Everyday for 3 months, taken once a day every morning mixed in Mt Dew then follow it with 1000mg of green tea extract (since Tim doesn't drink coffee) and 1000mg of Vitamin B1." Maybe the addition of EGCG or vanadium is the next step in the DCA protocol.
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Using DCA and a fat metabolism blocker in combination:
DCA is doing some great things for people, we still see cases in which the cancers do not respond, or respond for a while and stop responding. One possibility is that the cancer has switched to fat metabolism. Simultaneously blocking fat metabolism while using DCA seems like a sensible approach.
Note: Curcumin and EGCG taken together is probably not a good idea. This study suggests that they act antagonistically when taken together. The paper suggests taking them sequentially. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. "CONCLUSIONS: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion." [Thanks to "Mack" on this link]
At least some fatty acid metabolism inhibitors interact with thiamine.This area needs more study. Here are some examples:
Cerulenin: The Action Mechanism of Cerulenin "The antifungal activity of cerulenin was not reversed by amino acids, and purine and pyrimidine derivatives, but it was reversed especially by ergocalciferol, and to a certain extent by retinol, thiamine, pantothenic acid, lauric acid and oleic acid."
Metformin:Does Metformin Interfere With Thiamine? "Recent letters call attention to the tendency of metformin to interfere with vitamin B12 function. Perhaps metformin antagonizes other vitamins as well. Phenformin, the relatively toxic predecessor of the metformin, exhibited antithiamine activity in laboratory animals. Because thiamine vitally participates in the entrance of glycolytic pyruvate into the mitochondrial Krebs cycle, I hypothesize that an antithiamine effect of metformin contributes to some cases of metformin-associated lactic acidosis. Perhaps, as in beriberi, thiamine should be administered in a large dose to patients who develop metformin-associated acidosis."
Ideas? Things to share? Let me know. Jim