Synergistic inhibition of metastatic melanoma by carvacrol and chloroquine: an in vitro and in silico investigation of apoptosis and molecular targets

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Abstract
The development of drug resistance remains a major obstacle in the treatment of metastatic melanoma, necessitating novel therapeutic strategies. Combining natural compounds with agents that disrupt cancer cell survival mechanisms, such as autophagy inhibitors, offers a promising approach. This study aimed to evaluate the potential synergy between the plant-derived monoterpene carvacrol and the autophagy inhibitor chloroquine against metastatic melanoma. The cytotoxic and proapoptotic effects of carvacrol, chloroquine, and their combination were investigated in the WM9 metastatic melanoma cell line using WST-1 assays and Annexin V/7-AAD flow cytometry. The nature of the drug interaction was quantified using the Q-value. In silico molecular docking was performed to identify potential protein targets and elucidate the mechanisms underlying the observed effects. While carvacrol monotherapy exhibited weak cytotoxicity, its combination with non-toxic concentrations of chloroquine resulted in a potent and synergistic reduction in WM9 cell viability. This enhanced cytotoxicity was attributed to a significant, synergistic induction of apoptosis. In silico analysis predicted that both carvacrol and chloroquine bind with high affinity to common molecular targets, including Insulin-Like Growth Factor 1 Receptor and Sirtuin-2. Chloroquine was also predicted to interact strongly with HSP90. Our findings demonstrate that chloroquine potentiates the anticancer activity of carvacrol in metastatic melanoma cells. The synergy observed is likely mediated by a multi-targeted mechanism involving the simultaneous disruption of key cancer survival and signaling pathways. This study establishes the carvacrol-chloroquine combination as a novel and effective strategy that warrants further preclinical investigation for the treatment of resistant melanoma.

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