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Aishwarya Subramanian
The life cycle of cells is a key piece of our understanding of cancer; as cells grow, they divide and produce two new “daughter” cells. For the cells to divide, grow and survive, it requires energy which they gain by metabolising glucose. However, every healthy cell that divides has a checkpoint. Imagine a traffic light that makes sure only a certain path allows for the cars to pass by while the rest of them are waiting; similarly, the cell checkpoints makes sure cells do not undergo excessive division. The same cannot be said in the case of a cancer cell.
A cancer cell is very different from a healthy cell, both morphologically and functionally. Cancer cells undergo a phenomenon called the Warburg Effect, wherein the cells consume more glucose than healthy cells. The glucose is metabolised through an oxygen independent mechanism, even when there is oxygen available, to provide a constant stream of ATP (energy). The cells also consume more glutamine, an amino acid used for protein synthesis, to help combat oxidative stress (2).
With the constant breakdown of glucose and glutamine, these cancer cells are able to produce the basic building blocks that are necessary for their growth and survival. While we know that cancer cells use much more glucose and glutamine than their healthy counterparts, finding a way to use this difference to treat cancer has been slow-moving.
Recent research has revealed that altering the cellular metabolism might be one of the ways that the cancer cells promote tumor progression and formation (2).
Because of this, a class of chemotherapeutics known as antifolates have been developed to target folic acid, which contributes to the production of nucleic acids. Without this folic acid, the cells are unable to divide as rapidly and tumor growth slows.
The successful development of antifolate drugs helped to illustrate the mechanism of anti-metabolic treatments. This helped to develop more potential anti-cancer agents which could help disrupt the nucleic acid synthesis process. Some of these drugs are gemcitabine and fludarabine, which are widely used in the treatment of diverse tumors.
Even with these widely used drugs there is a constant effort to generate new drugs to target cancer cell metabolism. However, there are some key challenges that are faced when directly targeting these metabolic pathways- 1. Since all cells rely on energy (ATP), there is a possibility that drugs that target metabolic pathways would have detrimental effects on normal tissues. 2. These cancer cells tend to develop resistance against such drugs since they target the specific metabolic components of the pathway and not the metabolic flux (the rate at which each metabolic component is consumed for energy production). 3. Most metabolic enzymes that are required for the breakdown of nutrients as a source of energy are not mutated in cancer cells, so targeting these enzymes still remains a challenge.
With more research on cancer cell metabolism, there is hope that metabolic enzymes could be potential target candidates, and recent developments have shown promising results in preclinical models of cancer. Of course, clinical trials on these drugs have yet to be held, but we can hope that one day this new class of drugs is able to provide an additional layer of cancer treatment(3).
Outside of therapeutics, however, cancer metabolism is showing promise in the role of a diagnostic tool, as we have discussed previously. One approach is to imaging technologies like the MRI, PET which can help the detection of the metabolite using non-invasive markers. The ability to quantitate the level of metabolite in the body will serve as a great step for early detection and can serve as a potential treatment strategy for the specific type of cancer(1).
References:
- Targeting Cancer Metabolism- Beverly A. Teicher, W. Marston Linehan, and Lee J. Helman doi: 10.1158/1078-0432.CCR-12-2587
- Targeting cancer metabolism – aiming at a tumour’s sweet-spot- Neil P. Jones, Almut Schulze – https://doi.org/10.1016/j.drudis.2011.12.017
- Targeting cancer metabolism-– a therapeutic window opens- Matthew G. Vander Heiden- https://doi.org/10.1038/nrd3504
Edited by Sara Musetti
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