This section delves deeper into the mechanisms by which Metformin acts as an anti-cancer medication. Notably, Metformin’s influence on mitochondrial energy metabolism shows significant efficacy against breast, prostate, pancreatic, lung, and hepatocellular carcinomas. This discussion will further explore Metformin’s mitochondrial biochemistry and its impact on cancer cells.
Metabolic Stress Induced by Metformin
Before diving into the details, it’s crucial to understand that Metformin induces metabolic stress on cells. While healthy cells can tolerate this stress, it is acutely fatal to cancer cells. Over time, this metabolic shock allows healthy cells to adapt and potentially function better, whereas cancer cells, which are metabolically fragile in their early stages, struggle to survive. Metformin’s key strategy is to induce a tolerable stressor, potentially preventing the development of neoplasia if administered early.
Mechanism of Action
Metformin enters cells via the OCT1 transporter. At high concentrations, it binds to mitochondrial complex 1, inhibiting its function. This inhibition reduces the efficiency of oxidative phosphorylation, leading to decreased ATP production and subsequent activation of AMPK, which suppresses mTOR, a protein required for cell proliferation.
Additionally, Metformin prevents acetyl-CoA from entering the tricarboxylic acid (TCA) cycle, limiting fat production. Lipids produced in the TCA cycle are essential for cancer growth; therefore, inhibiting fat formation helps stop cancer progression.
Metformin also increases the expression ratio of BAX (pro-apoptotic) to BCL2 (anti-apoptotic), raising the likelihood of programmed cell death (apoptosis). The increase in BAX expression activates cytochrome C, which in turn activates the caspase 9/3/7 system, ultimately leading to cell death.
Balancing Cellular Respiration
It’s essential to note that Metformin does not entirely shut down cellular respiration. Such an outcome would be detrimental as it would kill all cells. Instead, the inhibition of mitochondrial complex 1 is thought to be a minor contributor to AMPK activation. Inhibition of mitochondrial glycerophosphate dehydrogenase might play a more significant role.
Metformin’s actions are designed to induce stress that healthy cells can tolerate but is fatal to metabolically compromised cells. This selective stress induction is beneficial for targeting and killing cancer cells.
Understanding the detailed biochemistry of Metformin reveals its potential as a powerful anti-cancer agent. By inducing metabolic stress and inhibiting key pathways essential for cancer cell survival and proliferation, Metformin offers a promising approach to cancer treatment and prevention. This knowledge enhances our ability to optimize Metformin’s use in oncology, providing hope for improved cancer therapies.
