Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G(1) Microbial Products against Melanoma Cells

Melanoma is the most serious type of skin cancer and remains highly drug-resistant. Therefore, the discovery of novel effective agents against melanoma is in high demand. Herein, we investigated the cytotoxic activities in melanoma cells and underlying molecular mechanisms of beauvericin (BEA) and its analogue beauvericin G(1) (BEA G(1)), which are cyclohexadepsipeptides isolated from fungi. BEA and BEA G(1) significantly suppressed the growth, clonogenicity, migration, and invasion of A375SM human melanoma cells and promoted caspase-dependent apoptosis through upregulation of death receptors, as well as modulation of pro- and anti-apoptotic Bcl-2 family members. Furthermore, the effects of BEA and BEA G(1) were associated with the suppression of multiple molecular targets that play crucial roles in melanoma oncogenesis, including ERK, JNK, p38, NF-κB, STAT3, and MITF. Notably, the cytotoxic efficacy of BEA G(1) against A375SM cells was stronger than that of BEA. These findings suggest that BEA and BEA G(1) can be further investigated as potent cytotoxic natural compounds for the suppression of melanoma progression.