Cutaneous melanoma is a fatal neoplasm with increasing incidence worldwide

Cutaneous melanoma is a fatal neoplasm with increasing incidence worldwide. Mutated proto-oncogene BRAF is the bona fide therapeutic target for about half of all melanomas. Regrettably, melanoma acquires resistance to BRAF inhibitors, e.g., vemurafenib (PLX4032) casting doubt on this promising melanoma targeted therapy. There is an urgent need for new therapeutic approaches to fight BRAF mutant melanoma. In this study, we explored the potential bioactivity of triterpenoid saponin cumingianoside A (CUMA), isolated from leaves and twigs of Dysoxylum cumingianum against PLX4032-resistant BRAFV600E mutant melanoma A375-R in vitro and in vivo. Our data show that CUMA treatment inhibited A375-R melanoma cell proliferation in a time- and dose-dependent manner. CUMA also suppressed the activity of CDK1/cyclin B1 complex and led to G2/M-phase arrest of A375-R cells. Furthermore, CUMA treatment resulted in induction of apoptosis as shown by the increased activation of caspase 3 and caspase 7, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), and activation of autophagy as shown by the increased expression of autophagy-related genes and increased formation of autophagosomes. Moreover, we found that CUMA treatment induced ER stress response mainly through the IRE1? axis and co-treatment with an ER stress inhibitor (4-PBA) could partially attenuate apoptosis and autophagy induced by CUMA. Importantly, orally administered CUMA as a single agent or in combination with PLX4032 exhibited strong tumor growth inhibition in a PLX4032-resistant A375-R xenograft mouse model, and with little toxicity. This is the first report to explore the anti-tumor activity of CUMA in vitro and in vivo mechanistically, and our results imply that this triterpenoid saponin may be suitable for development into an anti-melanoma agent.
Keywords: BRAF inhibitor-resistant melanoma, triterpenoid saponin, cumingianoside A apoptosis, ER stress, autophagy