Combination of Nexrutine and Docetaxel suppresses NFκB-mediated activation of c-FLIP

Abstract

Lack of effective options following failure to conventional chemotherapeutic agent such as Docetaxel is a major clinical challenge in the management of prostate cancer. These observations underscore the need for deciphering the underlying mechanism of docetaxel resistance to enable the development of effective therapeutic approaches. We observed up regulation of the anti-apoptotic protein c-FLIP and its up stream regulators including receptor tyrosine kinase RON and transcription factor NFκB (p65) in tumors obtained from metastatic prostate cancer patients. We also observed significant downregulation of these molecules in prostate tumors isolated from patients treated with docetaxel as first line therapy. Further, we identified the over the counter anti-inflammatory agent, Nexrutine suppresses c-FLIP protein levels and expression in androgen-independent prostate cancer cells (PC-3). Remarkably, the observed decreased levels of c-FLIP were further reduced in combination with docetaxel. Transient expression assays coupled with electrophoretic mobility shift and DNA affinity protein assay revealed that Nexrutine and docetaxel suppresses c-FLIP promoter activity by preventing p65 binding. Notably, Nexrutine in combination with docetaxel abolished binding of p65 to the c-FLIP promoter sequence containing NFκB binding sites. Biologically, these alterations resulted in reduced growth of PC-3 cells. Taken together, these observations suggest the utility of RON, p65 and c-FLIP as potential markers to predict response to docetaxel treatment. Furthermore, our results also identified Nexrutine as an agent to potentiate the therapeutic response of docetaxel by suppressing activation of c-FLIP and its upstream regulators. This article is protected by copyright. All rights reserved

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