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Conventional chemotherapy induces significant toxicity, leading to serious side effects; thus, an effective strategy to counter this would be to use a combination of drugs that have unrelated mechanisms of action and drug resistance. Doxorubicin, a widely used chemotherapeutic drug, has adverse side effects; thus, it is crucial to reduce its toxicity to improve its therapeutic regimen. Cancer cells vitally differ from normal cells with respect to their metabolism, and the use of metabolic modulators is expected to proximally compensate the various manifestations of cancer. In this study, doxorubicin was used in combination with a dual-hit metabolic modulator, LDCA, with the postulation that this adroit targeting of cancer cells would exert potent therapeutic effects. The results demonstrated that this combination synergistically enhanced the growth inhibition and induced mitochondria-mediated apoptosis by recruiting the caspase cascade, restricting migration, and obviating the clonogenic outgrowth potential of melanoma cells. Interestingly, the combination specifically dampened melanoma cell viability, but spared the normal population; this suggested its low toxicity profile. Furthermore, in the preclinical model of murine melanoma, combination treatment thwarted tumor growth kinetics to restrain oncogenic progression, thus accentuating survival. Comprehensively, we have demonstrated the promising therapeutic potential of the combination of doxorubicin and LDCA in the expanding chapter of combinatorial therapy.

The dual-hit metabolic modulator LDCA synergistically potentiates doxorubicin to selectively combat cancer-associated hallmarks