BACKGROUND: The identification and use of novel compounds alone or in combination hold promise for the fight against NRAS mutant melanoma.

MATERIAL AND METHODS: We screened a kinase-specific inhibitor library through combining it with α-Mangostin in NRAS mutant melanoma cell line, and verified the enhancing effect of α-Mangostin through inhibition of the tumorigenesis pathway.

RESULTS: Within the kinase inhibitors, retinoic acid showed a significant synergistic effect with α-Mangostin. α-Mangostin also can reverse the drug resistance of retinoic acid in RARa siRNA-transduced sk-mel-2 cells. Colony assay, TUNEL staining, and the expressions of several apoptosis-related genes revealed that a-Mangostin enhanced the effect of retinoic acid-induced apoptosis. The combination treatment resulted in marked induction of ROS generation and inhibition of the AKT/S6 pathway.

CONCLUSIONS: These results indicate that the combination of these novel natural agents with retinoid acid may be clinically effective in NRAS mutant melanoma.

Keywords: Biological Products - therapeutic use, Down-Regulation - drug effects, GTP Phosphohydrolases - genetics, Gene Expression Regulation, Neoplastic - drug effects, Melanoma - pathology, Membrane Proteins - genetics, Mutation - genetics, Phosphorylation - drug effects, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins c-akt - metabolism, Reactive Oxygen Species - metabolism, Reproducibility of Results, Signal Transduction - drug effects, Tretinoin - therapeutic use, Xanthones - therapeutic use