Figure 3.

An illustration of the combination effect of H₂S donors, metformin, and simvastatin in facilitating acidification-induced cell death. Metformin inhibits mitochondria complex 1, leading to the accumulation of AMP and the downstream activation of AMPK pathway. Next, AMPK increases NADPH which in turn facilitates the conversion of pyruvate into lactic acid thereby increasing intracellular acidity. H₂S donors promote glycolysis and inhibit the activities of intracellular acidity regulators (NHEs and EAs). On the other hand, simvastatin prevents the exportation of lactate by inhibiting MCT-4. Together, all these processes cause cell death by decreasing intracellular pH. (AMPK: AMP-activated protein kinase; NADPH: nicotinamide adenine dinucleotide phosphate; NHE_S: sodium/proton exchangers; AEs: anion exchangers; MCT-4: monocarboxylate transporter-4).