NSAID Sulindac and Its Analog Bind RXR alpha and Inhibit RXR alpha-Dependent AKT Signaling

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-alpha (RXR alpha). We identified an N-terminally truncated RXR alpha (tRXR alpha) in several cancer cell lines and primary tumors, which interacted with the p85 alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNF alpha) promoted tRXR alpha. interaction with the p85 alpha, activating PI3K/AKT signaling. When combined with TNF alpha, Sulindac inhibited TNF alpha-induced tRXR alpha/p85 alpha interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXR alpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXR alpha-dependent AKT activation and tRXR alpha tumor growth in animals.National Institutes of Health [CA109345, CA140980, GM089927, GM062848]; Susan G. Komen Breast Cancer Foundation ; California Breast Cancer Research Program ; U.S. Army Medical Research and Material Command ; California Tobacco-Related Diseases Research Program ; Xiamen University ; 863 Program [2007aa09z404]; National Science Foundation [30971445, 30931160431