Tuesday, February 01, 2011

Metabolic Manipulation: A New Cancer Treatment Paradigm

Aspirin: inhibits the activation of a transcription factor that leads to cancer cell growth and inflammatory response (via cytokines IL-1 and IL-6).

Cimetidine: prevents histamine binding and indirectly enhances local anti-tumor response via IL-18 signaling to the immune system's natural killer and T cells.

Dichloracetate (DCA): DCA inhibits pyruvate dehydrogenase kinase (PDK), an inhibitor of pyruvate dehydrogenase, a key enzyme in glucose metabolism. DCA preferentially shifts glucose metabolism in cancer cells from glycolysis to glucose oxidation, reversing the unique aerobic glycolysis found in solid tumors and induces apoptosis. [orphan drug used to treat lactic acidosis].

Metformin: suppresses the AMPK/mTOR/S6K1 axis and several protein kinases. Metformin may also specifically target the cancer-initiating stem cells, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion root hypothesis). [Beware Cimetidine and Metformin are secreted by the same cation pump in renal tubules]

Low Fructose Diet: Pancreatic cancers use the sugar fructose to activate a key cellular pathway that drives cell division

Black Cumin Seed: Nigella sativa oil containing thymoquinone has been demonstrated to reduce the growth and size of tumors in rats.

Co-Enzyme Q10:
lipid soluble antioxidant that stimulates the immune system leading to higher antibody levels, greater numbers and/or activities of macrophages and T cells and increased resistance to infection.

Vitamin C and NAC: both human lymphoma or human liver cancer cells which produce high levels of free radicals were suppressed with these antioxidants in a DNA damage independent mechanism. Researchers believe that the antioxidants destabilizing a tumor's ability to grow under oxygen-starved conditions.

Desferrioxamine: iron chelator that binds iron and limits a key limiting metabolite needed for tumor growth. High iron levels also inhibit the immune system.

Up to now, traditional cancer treatment involves a cocktail of super-expensive cytotoxic chemotherapy drugs that target rapidly dividing cells. The aim of our current treatment strategy is to give the patient just the right dose of poison that will kill the cancer but not the patient. With only a few exceptions, the focus on most cancer treatments has been to target rapidly dividing cells by directly damaging DNA (cisplatin, doxorubicin, cyclophosphamide), indirectly damaging DNA (MTX, 5-FU), inhibiting DNA repair enzymes (etoposide), or by targeting key enzymes necessary for cellular division (paclitaxel, vincristin). The problem with this paradigm is that this selective killing isn't selective enough. However, this strategy is not the only one out there.

Another promising paradigm for cancer treatment would be to focus on the manipulation of metabolic pathways of cancer cells. Scientists are discovering that cancer cell metabolic pathways may be unique or at least more limited than normal cells. And it is these metabolic limitations that could be exploited. First off, we know that all cells in the body can generate energy using several anaerobic and aerobic mechanisms. These metabolic pathways include: anaerobic glycolysis, aerobic respiration (TCA cycle), oxidative phosphorylation, lipolysis (ketogenic), and gluconeogenesis,

One of the first identified biochemical hallmarks of tumor cells was a shift in glucose metabolism from aerobic oxidative phosphorylation to anaerobic glycolysis (the "Warburg effect" or "Warburg hypothesis"). Now, scientists have revealed that cancer cellular functions and growth are primarily dependent upon the anaerobic metabolism of glucose, fructose and lipid (lypolysis). Aerobic respiration via the TCA-cycle and Oxidative phosphorylation is very complex and requires intact mitochondria. Because of that complexity, mutated cancer cells can rarely depend on aerobic metabolism for energy. Instead, they rely primarily on the much simpler anaerobic glycolysis; using glucose and fructose as fuel. Otto Warburg, 1931 Nobel Laureate, was first to measure and explain the mechanisms behind the large amounts of lactic acid produced by cancer cells.

However, when glucose levels are low, cancer cells are in a pinch. They can't do aerobic respiration, so lacking glucose, they instead turn to ketogenic lipolysis for energy. But cancer cells have the complex machinery needed to transport lipids into the cell. Instead, in a low glucose environment, they use their damaged oxidative phosphorylation pathway and other pathways to generate high levels of reactive oxygen species (ROS). These ROS are then secreted into the cells microenvironment where they damage nearby cells. In this way, cancer cells begin to parasitize nearby cells and literally eat their host alive.

New studies suggest that cancer cells may not generate ROS themselves, but instead, reprogram neighboring stromal fibroblast cells to generate high amounts of ROS for them. The ROS then damage neighboring cells resulting in lipid peroxidation, and the production of lactate, and ketones which the cancer cells can use for energy. Through this mechanism, tumors do not need much of a blood supply. Understanding how cancer cells metabolize energy, we can now develop new strategies to kill them.

Together, the medicines, herbs, and vitamins listed above should do two things. First, a low-fructose diet together with Metformin and DCA will serve to inhibit both gluconeogenesis and anerobic glycolysis and force cancer cells into lipolysis. While we want the force the cancer into a ketogenic state, a ketogenic diet and dehydration are discouraged because scientists believe that cancer cells may thrive on lactic acid and ketones. That said, this first strategy should force the cancer cells to depend primarily on lipolysis for energy.

Next, iron chelation is added to inhibit ROS formation. Antioxidants like Vitamin C, E, Co-enzyme Q10, and Cumin are added to prevent remaining ROS oxidative damage to surrounding tissues. Also, anti-inflammatory and immune modulating agents such as aspirin, cimetidine could be added to reduce inflammation and boost cellular and humeral immunity. All together, cancer cells should not be left with any alternative energy alternatives. Then, at that point, cancer cells would turn cannibalistic and should undergo autophagy.

The hope is that a paradigm focused on metabolic manipulation, will be not only more effective at curing cancer, but will avoid the terrible side effects of traditional cytotoxic chemotherapy. However, until this new paradigm is proven, it will most likely be necessary to test this new paradigm in between rounds of traditional cytotoxic chemotherapy.



Anonymous said...

Wow, I was thinking the simular outcome with the use of metformin and DCA.

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Anonymous said...

Possible typo in 4th paragraph.
"But cancer cells have the complex machinery ..." maybe should say "...do not have..."

tahera said...

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