Scorpion venom peptide S6540 induces caspase-independent apoptosis in non-small cell lung cancer A549 cells

Lung cancer remains the leading cause of cancer death. Despite being effective in cancer treatment, the limitation of conventional chemotherapies that involve non-selective cytotoxicity and drug resistance leads to the urgent need for alternatives. Herein, we present the antitumor activity of S6540, a non-disulfide-bridge peptide identified from the venom gland of Superstitionia donensis. S6540 was found to enter the cell, target its mitochondria, induce caspase-independent apoptosis, and finally suppress the cell viability of A549 cells. Furthermore, S6540 could reduce the presence of Bcl-2 in mitochondrial membranes, induce apoptosis-inducing factor nuclear translocation, and suppress PI3K/Akt signaling pathway activation. In vivo, S6540 suppressed tumor growth in the A549 tumor xenograft model with a lower negative effect than Cisplatin. Accordingly, this study shed light on the antitumor mechanism of S6540, which may contribute to its further development as a potential agent in treating lung cancer cells.