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.