Investigating Metformin & Syrosingopine’s Synthetic Lethality in PC3 & THP-1 Cancer Cell Lines

Abstract

The oral antidiabetic, metformin, has been documented to have antineoplastic activity in various cancer cell lines, associated with the inhibition of mitochondrial complex I. However, pre-clinical studies have struggled to demonstrate such antineoplastic activity utilising metformin concentrations attainable with standard antidiabetic dosing. Research has revealed that metformin combined with the anti-hypertensive drug, syrosingopine, lowers metformin’s therapeutic threshold and sensitizes cancer cells to killing, by inhibiting monocarboxylate transporters (MCT)1/MCT4. The potent interaction between these drugs elicits a synthetic lethality, specific to transformed cells. This preliminary study aimed to investigate metformin’s antineoplastic effects and its synergistic relationship with syrosingopine by measuring cell viability and extracellular lactate in PC3 (adherent) and THP-1 (suspension) cancer cell lines. Overall, the PC3 cell line responded better to treatment with combined doses of metformin and syrosingopine, or either drug alone; however, synthetic lethality was not observed in either cell line. In both cell lines, the interaction between metformin and syrosingopine was not statistically significant in the cell viability assays (p>0.05). Analysis of MCT1/MCT4 inhibition through the measurement of extracellular lactate was not statistically significant (p>0.05) and proved inconclusive. Additionally, the nature of the cell line, adherent or suspension, was statistically significant (p<0.05) in some treatment groups, suggesting that this may play a role in the efficacy of the drug treatments. Further research is necessary to better understand the underlying cellular mechanisms of metformin and syrosingopine’s synthetic lethality, and syrosingopine’s MCT1/MCT4 inhibition. Future research should focus on achieving metformin doses capable of exhibiting antineoplastic effects in vivo.