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Using Nutrient Deprivation as a Strategy for Cancer Therapy

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Dr. Agus explains why people are "cancering" (note that a verb instead of a noun is used here to account for its dynamic nature) in his book[1] by saying:


The body has several pathways leading to cancer.


While we may find a way to block one molecular pathway in our attempts to treat the disease, that doesn't mean cancer can't find its way down another path, which it usually does in an efficient fashion, unfortunately.


It is known that cancer cells need a lot of nutrients to multiply and survive. If starved for fuel, the cancer cells can begin consuming themselves in a process called autophagy—accompanied by other biochemical events that lead to the cells' death by a natural process called apoptosis. However, there are multiple metabolic pathways which used by cancer cells to fuel themselves. For example, two well-known fuels that can promote tumor's growth are:

  • Glucose
  • Glutamine.


Glucose


Cancer cells grow so fast that they can outstrip their blood supply, leaving them short of oxygen. A hallmark feature of tumorigenesis is the shift of cellular metabolism from oxidative phosphorylation to aerobic glycolysis, the so called Warburg effect, which provides a growth advantage to cancer cells in the microenvironment[2,3].


Glycolysis is the metabolic pathway that converts glucose into pyruvate. Malignant rapidly growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin.

This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2-18F-2-deoxyglucose (FDG) (a radioactive modified hexokinase substrate) with positron emission tomography (PET).[4][5]


There are also ongoing researches to treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways.[6,7]


Glutamine


Glutamine is one of the 20 amino acids, which is one of the building blocks for protein synthesis. Besides that, it is also a main cellular fuel source next to glucose. From previous researches, it's known that some cancer cells can survive in vitro without glucose at all if supplied with glutamine and nucleosides. [11-13]


The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis[6,7]. However, Lazebnik et al. found that depletion of glucose also killed normal human cells by a mechanism different from apoptosis.[9]


Similarly, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis. Their results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.


Conclusion


Because chronic energy restriction proves to be difficult to implement as an anti-tumor strategy, energy restriction-mimetic agents (ERMAs)[6,7] have received wide attention as they can mimic the beneficial effects of energy restriction through the inhibition of glucose or glutamine utilization in cancer cells. Now we know there are multiple metabolic pathways utilized by cancer cells to grow fast. Maybe we just need to find multiple ERMAs to block all these metabolic pathways without impacting normal cells too much.  For example, Dr. D'Agostino[17] has been advocating using ketogenic diet[19] as a cancer treatment strategy by forcing body cells to utilize ketone bodies (which most cancer cells cannot utilize) instead of glucose as fuel source.


Due to cancer cell's ability to grow fast, it has another hallmark feature—ability to evolve over time. As Dr. Agus described:[1]


Every time a new generation of cancer cells is born, those cells harbor new mutations—mutations that go beyond those already present in the genes that are supposed to regulate growth. Just as resistant strains of bacteria can result from antibiotic use, anticancer drugs can produce resistant cancer cells.


Therefore, our battle against cancer is a tough one. And we still have a long way to go.


References

  1. The End of Illness by David B. Agus, MD
  2. Kroemer, G., and Pouyssegur, J. (2008) Cancer Cell 13, 472-482
  3. Kim, J. W., and Dang, C. V. (2006) Cancer Res. 66, 8927-8930
  4. Positron Emission Tomography (PET) imaging
  5. P:ositron-emission tomography with [18F]fluorodeoxyglucose
  6. New Agent Chokes Off Energy Supply, Kills Cancer Cells
  7. ENERGY RESTRICTION-MIMETIC AGENTS INDUCE APOPTOSIS IN PROSTATE CANCER CELLS, IN PART, THROUGH EPIGENETIC ACTIVATION OF KLF6 TUMOR SUPPRESSOR GENE EXPRESSION
  8. Glutamine (Wikipedia)
  9. Yuneva, M.; Zamboni, N.; Oefner, P.; Sachidanandam, R.; Lazebnik, Y. (2007). "Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells". The Journal of Cell Biology 178 (1): 93–105.
  10. What's feeding cancer cells?
  11. Reitzer, L.J., B.M. Wice, and D. Kennell. 1979. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 254:2669–2676.
  12. Wice, B.M., L.J. Reitzer, and D. Kennell. 1981. The continuous growth of vertebrate cells in the absence of sugar. J. Biol. Chem. 256:7812–7819.
  13. Linker, W., M. Loffler, and F. Schneider. 1985. Uridine, but not cytidine can sustain growth of Ehrlich ascites tumor cells in glucose-deprived medium with altered proliferation kinetics. Eur. J. Cell Biol. 36:176–181.
  14. Eat Less Live Longer (Travel and Health)
    • Calorie restriction, or, simply, CR, which we know works in extending the life span of mice, rats, fruit, flies, earthworms, yeast, and many hope, humans
  15. Excess Sugar Linked to Cancer
  16. Sugar Activates Oncogenes in Tumors
    • "Our study shows that sugar activates oncogenes in the tumor, which then promote insulin sensitivity, meaning that the exorbitant glucose levels in the blood pour into the tumor, having nowhere else to go in the insulin-resistant body." said scientists from the Icahn School of Medicine at Mount Sinai in New York City.
  17. Dr. Mercola and Dr. D'Agostino on Ketogenic Diet (video)
    • They are talking about a cancer treatment strategy integrating a ketogenic diet with hyperbaric oxygen therapy, which is deadly to cancer cells by starving them of their fuel source.
  18. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer
  19. Ketogenic Diet Resource
  20. Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–1035.
  21. Ketone bodies (Princeton University)
    • Ketone bodies can be used for energy. Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle.
  22. Fat for Fuel (Dr. Mercola)
  23. Cancer generated lactic acid: Novel therapeutic approach

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