Nimbolide enhances the antitumor effect of docetaxel via abrogation of the NF-κB signaling pathway in prostate cancer preclinical models

Abstract

Prostate cancer is the second most frequent type of cancer that affects men. Docetaxel (DTX) administration is the front-line therapy for patients with advanced prostate cancer and unfortunately, half of these patients develop resistance to DTX which could be due to its ability to activate the NF-κB pathway. The combinational effect of DTX and nimbolide on proliferation, apoptosis, activation of NF-κB, DNA binding ability of NF-κB, and expression of NF-κB-targeted gene products was investigated. The antitumor and antimetastatic effect of DTX or NL alone or in combination was also examined. The co-administration of NL and DTX resulted in a significant loss of cell viability with enhanced apoptosis in DTX-sensitive/resistant prostate cancer cells. NL abrogated DTX-triggered NF-κB activation and expression of its downstream antiapoptotic factors (survivin, Bcl-2, and XIAP). The combination of NL and DTX significantly reduced the DNA binding ability of NF-κB in both cell types. NL significantly enhanced the antitumor effect of DTX and reduced metastases in orthotopic models of prostate cancer. NL abolishes DTX-induced-NF-κB activation to counteract cell proliferation, tumor growth, and metastasis in the prostate cancer models.

Keywords: Docetaxel; Drug resistance; NF-κB; Nimbolide; Prostate cancer.