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Cancer Cell. 2010 Jun 15;17(6):560-73. doi: 10.1016/j.ccr.2010.04.023.

NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.

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1
Institute for Biomedical Research, Xiamen University, Xiamen, Fujian 361005, China.

Abstract

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 (RXRalpha). We identified an N-terminally truncated RXRalpha (tRXRalpha) in several cancer cell lines and primary tumors, which interacted with the p85alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNFalpha) promoted tRXRalpha interaction with the p85alpha, activating PI3K/AKT signaling. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha 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 RXRalpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRalpha-dependent AKT activation and tRXRalpha tumor growth in animals.

PMID:
20541701
PMCID:
PMC2907921
DOI:
10.1016/j.ccr.2010.04.023
[Indexed for MEDLINE]
Free PMC Article

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