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

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.

• Authors: Hu Zhou, Wen Liu, Ying Su, Zhen Wei, Jie Liu, Siva Kumar Kolluri, Hua Wu, Yu Cao, Jiebo Chen, Yin Wu, Tingdong Yan, Xihua Cao, Weiwei Gao, Andrei Molotkov, Fuquan Jiang, Wen-Gang Li, Bingzhen Lin, Hai-Ping Zhang, Jinghua Yu, Shi-Peng Luo, Jin-Zhang Zeng, Gregg Duester, Pei-Qiang Huang, Xiao-Kun Zhang
• Journal: Cancer cell (Cancer Cell) Vol. 17 Issue 6 Pg. 560-73 (Jun 15 2010) ISSN: 1878-3686 [Electronic] United States
• PMID: 20541701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Retinoid X Receptor alpha
• Tumor Necrosis Factor-alpha
• bcl-2-Associated X Protein
• Sulindac
• Tretinoin
• Prostaglandin-Endoperoxide Synthases
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (metabolism, pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Cytoplasm (metabolism)
• Dinoprostone (metabolism)
• Drug Design
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostaglandin-Endoperoxide Synthases (drug effects, metabolism)
• Protein Binding (drug effects, physiology)
• Protein Processing, Post-Translational (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Retinoid X Receptor alpha (antagonists & inhibitors, genetics, metabolism)
• Sequence Deletion (physiology)
• Signal Transduction (drug effects, physiology)
• Sulindac (analogs & derivatives, metabolism, pharmacology, therapeutic use)
• Transcriptional Activation (drug effects)
• Transfection
• Tretinoin (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (genetics, metabolism)