What are Substrates?
In the context of
biochemistry, substrates are molecules upon which enzymes act. They bind to the enzyme's active site, undergoing a chemical transformation to become the product. In
cancer biology, substrates often refer to molecules involved in cellular processes that may be hijacked by cancer cells to promote their growth and survival.
Role of Substrates in Cancer Metabolism
Cancer cells exhibit altered metabolism, often referred to as the
Warburg effect. They preferentially use
glucose for
glycolysis even under aerobic conditions, producing lactate. This metabolic reprogramming provides the necessary substrates for biosynthetic pathways, aiding in rapid cell proliferation. Other substrates like
glutamine are also critical as they support the tricarboxylic acid (TCA) cycle and nucleotide synthesis.
Why Are Substrates Important in Cancer Therapy?
Targeting the metabolic pathways and substrates that cancer cells rely on can be a potential therapeutic strategy. Inhibitors of glycolytic enzymes, for instance, can limit the availability of critical substrates, impeding cancer cell growth. Drugs targeting the
TCA cycle or
amino acid metabolism also show promise in disrupting the metabolic flexibility of cancer cells.
Examples of Substrate-Targeted Therapies
Several therapies are under investigation or in clinical use targeting metabolic substrates: Metformin: Originally an anti-diabetic drug, metformin inhibits mitochondrial complex I, affecting ATP production and reducing glucose availability.
IDH Inhibitors: Mutations in isocitrate dehydrogenase (IDH) produce an oncometabolite, 2-hydroxyglutarate. Inhibitors targeting mutant IDH can reduce this substrate, impacting cancer cell metabolism.
Glutaminase Inhibitors: Drugs like CB-839 inhibit glutaminase, thereby reducing glutamine metabolism, essential for cancer cell survival.
Challenges in Targeting Substrates
Targeting substrates in cancer therapy is not without challenges. Cancer cells can exhibit metabolic plasticity, adapting to the inhibition of one pathway by upregulating alternative pathways. Additionally, normal cells also require these substrates for their function, leading to potential
toxicity and side effects. Therefore, achieving a therapeutic window that selectively targets cancer cells while sparing normal cells is critical.
Future Directions
Ongoing research aims to better understand the metabolic dependencies of different cancer types. Advances in
metabolomics and
genomics are crucial for identifying novel substrates and pathways that can be targeted. Personalized medicine approaches, combining metabolic inhibitors with other therapies, hold promise for more effective cancer treatments.
