Abstract 3786: Gambogic acid inhibits chemokine receptor CXCR4 signaling pathways and osteoclastogenesis in multiple myeloma

Abstract

Abstract Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of CXCR4 mRNA expression, inhibition of nuclear factor-kappa B (NF-κB) activity, and suppression of p65 binding at CXCR4 promoter analyzed by quantitative chromatin immunoprecipitation (qChIP) assay. Suppression of CXCR4 expression by GA correlated with both inhibition of SDF-1α-induced invasion of MM cells. GA also inhibited phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA suppressed the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. Finally, we found that MM cells, induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and thus has a strong potential to suppress osteoclastogenesis mediated by MM cells. Citation Format: Manoj K. Pandey, Vijay P. Kale, Chunhua Song, Shen-shu Sung, Arun K. Sharma, Sinisa Dovat, Shantu G. Amin. Gambogic acid inhibits chemokine receptor CXCR4 signaling pathways and osteoclastogenesis in multiple myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3786. doi:10.1158/1538-7445.AM2014-3786