Varshit Dusad
Methotrexate is one of the earliest drug discovered for treatment of cancer. It is listed by WHO as one of the essential medicines and has been used to treat various forms of cancer. Methotrexate has had such broad success across cancer subtypes due to its unique mechanism of action. Inside tumors, it attacks a unique choke point, the rapid proliferation of cancer cells, by mimicking chemicals cancer cells need to survive. It is an “antimetabolite,” a chemical compound resembling a natural metabolite in structure but not in function. By virtue of its structural similarity to naturally found folate, it is able to bind an enzyme called “Dihydrofolate reductase” which is critical for making new DNA, a necessary step in tumor growth. Simply put, methotrexate obstructs cancer’s capability to replicate by blocking the production one of the key ingredients used for building new DNA. If no new DNA is produced, the cancer cells cannot rapidly duplicate, and therefore die. Hacking the unique traits of cancer metabolism for its treatment has given way to many drugs like methotrexate for successful cancer treatment.
Despite the early successes in the field of cancer metabolism, it is often overshadowed by enthusiasm over cancer genetics, the study of genetic differences in cancer cells compared to healthy cells. It was believed that cancer metabolism reflected the unique fingerprint of cancer but was insufficient to provide many useful insights into the functional mechanism and origin of cancer. However, that perspective is changing with new discoveries in cancer metabolism which show that it is indeed an active player growth and spread of cancer.
One of the oldest and most pivotal discoveries about cancer metabolism was made almost a century ago by Nobel Laureate Otto Warburg. He observed that cancer cells produce much of their energy by using anaerobic fermentation (without the presence of oxygen) instead of oxygen-dependent aerobic pathways. This phenomenon has since been named the Warburg effect. While both the pathways exist in both normal and cancer cells to generate energy, normal cells utilize the oxygen-dependent pathway (also called oxidative phosphorylation) because it is many times more efficient than fermentation. This is surprising for two reasons, the first being that cancer would prefer to opt for an inefficient energy production pathway when a more efficient one is readily available. Second, due to the increased rate of proliferation and metastasis (attack of cancer cells on neighboring tissues), their energetic requirement should also be higher. This juxtaposition between high energy demand and choosing a low energy-yielding pathway is indeed surprising!
The reasons for the surprising bioenergetics of cancer cells becomes clear when more of their peculiar metabolic behaviors are observed. Tumors gobble up nutrients left and right from whatever source they can use. They enhance their glucose and glutamine uptake, engulf neighboring cells and metabolize them for nutrients and in general absorb any macromolecule in the bloodstream which can be broken down into biosynthetic precursors of cells. This gluttonous appetite of cancer can be traced back to its demand for rapid growth. The aberrant choice of fermentation over aerobic respiration is another key piece in this puzzle.
In normal cells, the prominent goal of glucose is to generate energy. The energy needs of cells also control the energy production. However, glucose has another role, which is to provide carbon molecules for biosynthesis of macromolecules requiring carbon. The first ten steps of aerobic respiration and biosynthesis reactions are the same and are collectively called glycolysis. In healthy cells, the glucose gets transported to mitochondria for respiration which also produces metabolites like NADH, which downregulates the glycolysis. Since cancer has a much higher demand for biosynthesis than it has for energy, it cannot afford to shut down glycolysis as soon as energy demand is fulfilled. Therefore, the glucose metabolism is shifted out of aerobic respiration to fermentation, because it helps in to keep running the glycolysis necessary for biosynthesis. Understanding this metabolic shift in cancer cells due to the pressure of rapid growth in nutrient scarce environment became the basis for targeting DNA synthesis pathway for chemotherapy. Many popular chemotherapeutic drugs like Methotrexate, Floxuridine, Gemcitabine, Hydroxycarbamide, etc. were all developed to target cancer’s hunger for growing faster.
Like the Warburg effect, many aspects of cancer metabolism indeed appear paradoxical at first glance. However, careful and patient investigations are revealing the importance of these changes and how they play an important role in promoting the intrinsic goals of cancer: survival and rapid growth. Cancer metabolism has become an active area of research with high expectations of providing biomarkers which can help to develop novel drugs for cancer treatment.
Works Discussed
Pavlova, N. N. & Thompson, C. B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 23, 27–47 (2016).
Ward, P. S. & Thompson, C. B. Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate. Cancer Cell 21, 297–308 (2012).
Image Credits
Artistic view of a simplified human metabolic network (human metabolome)
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