Synergism of metabolic modulators Bet-CA and LDCA: a rational combinatorial approach to selectively combat cancer associated hallmark traits

Abstract

Malignant cells exhibit metabolic alterations contrastingly from normal cells and hence, targeting cancer metabolism is being considered as a key strategy for fabricating combinatorial therapeutic regimens that would not only exclude the adverse side-effects of conventional chemotherapy, but also bypass the phenomenon of chemoresistance. Herein, Bet-CA, a co-drug that hampers mitochondrial membrane potential to counter apoptosis resistance, angiogenesis and metastasis was used in combination with a ‘dual-hit’ metabolic modulator LDCA that inhibits lactate dehydrogenase A (LDH-A) enzyme activity to rigorously alter mitochondrial bioenergetics and concomitantly promote apoptosis in cancer cells. Combination of metabolic modulators Bet-CA and LDCA demonstrated synergistic growth inhibitory mechanisms, specifically in melanoma cells. Furthermore, combination synergistically and selectively depleted mitochondrial membrane potential and exerted reactive oxygen species (ROS) generation to consequently promote caspase mediated cell death. Importantly, in a preclinical model of melanoma, combination stringently limited tumor progression without significant toxic manifestations. Thus, with a clear safety profile, our studies present a comprehensive rationale for the efficacy and prospectus of using combinatorial therapy of metabolic modulators and offer a one of a kind solution to counter the enduring challenge of malignancy.