Malignant melanoma is highly metastatic and resistant to conventional therapies. Although numerous clinical approaches for treating melanoma have been adopted, none led to a remarkable therapeutic effect. Recently new drugs have been developed for treatment of metastatic melanoma, and hold great promise; however complete effects are still distant dream because of resistance. We have learnt that the most aggressive melanomas are generally resistant to strategies which target one signaling pathway. Thus an agent targeting multiple signaling pathways would maximize therapeutic outcome. We have identified one such agent named as gambogic acid (GA) that is natural and derived from medicinal plant Garcinia hanburyi (also called mangosteen or kokum). Moreover this agent has a potential to target several pathways responsible for survival and chemoresistance of several cancers including melanoma. Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been associated with inferior survival, poor prognosis, chemoresistance and metastasis of malignant melanoma. We, therefore, investigated whether GA could inhibit CXCR4 signaling and suppress invasion of malignant melanoma cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on melanoma cells in a dose- and time-dependent manner. Suppression of CXCR4 expression by GA correlated with both inhibition of SDF-1α-induced invasion of melanoma cells. GA also inhibited expression of MMP-9, VEGF, c-Myc and phosphorylation of Erk1/2 in melanoma cells. Importantly, GA markedly enhances the efficacy of PLX-4032 and dacarbazine against melanoma cells.

Citation Format: Manoj K. Pandey, Deepkamal Karelia, Vijay P. Kale, Krishne Gowda, Arun K. Sharma, Rogerio I. Neves, Shantu G. Amin. Targeting of chemokine receptor CXCR4 inhibits invasion and sensitizes melanoma cells to chemotherapeutic agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4467. doi:10.1158/1538-7445.AM2015-4467

©2015 American Association for Cancer Research.
2015