Synergistic inhibition of cell proliferation by combined targeting with kinase inhibitors and dietary xanthone is a promising strategy for melanoma treatment

Summary α‐Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single‐agent therapy for malignant melanoma ( MM ), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase ( GSK )‐3 inhibitor CHIR 99021, and rapamycin, in combination with a dietary xanthone, α‐mangostin, by screening from a kinase inhibitor library for melanogenesis in SK ‐ MEL ‐2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis‐related proteins. We also explored the molecular mechanisms for the apoptosis‐inducing effects reported. We found a marked synergistic effect of CHIR 99021 or rapamycin in combination with α‐mangostin, which we verified through apoptosis‐related methods. These data provide a strong rationale for the use of α‐mangostin as an adjunct to GSK ‐3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α‐mangostin might be inhibition of phosphatidylinositol 3‐kinase/ AKT signalling and autophagy, and induction of reactive oxygen species generation.