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Paclitaxel Directly Binds to Bcl-2 and Functionally Mimics Activity of Nur77

¹ Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy; ² Department of Oncology, Catholic University of the Sacred Heart, Campobasso, Italy; ³ Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy; ⁴ Department of Natural Products, University of Napoli Federico II, Napoli, Italy; and ⁵ NatSynDrugs, Department of Chemistry, University of Siena, Siena, Italy

Requests for reprints: Cristiano Ferlini, Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, L.go A. Gemelli 8, Rome, Italy 00168. Phone: 39-635502407; Fax: 39-635508736; E-mail: cferlini{at}rm.unicatt.it.

Key Words: Drug resistance • Mitochondria • Paclitaxel

We reported previously that Bcl-2 is paradoxically down-regulated in paclitaxel-resistant cancer cells. We reveal here that paclitaxel directly targets Bcl-2 in the loop domain, thereby facilitating the initiation of apoptosis. Molecular modeling revealed an extraordinary similarity between the paclitaxel binding sites in Bcl-2 and β-tubulin, leading us to speculate that paclitaxel could be mimetic of an endogenous peptide ligand, which binds both proteins. We tested the hypothesis that paclitaxel mimics Nur77, which, like paclitaxel, changes the function of Bcl-2. This premise was confirmed by Nur77 interacting with both paclitaxel targets (Bcl-2 and β-tubulin) and a peptide sequence mimicking the Nur77 structural region, thus reproducing the paclitaxel-like effects of tubulin polymerization and opening the permeability transition pore channel in mitochondria. This discovery could help in the development of novel anticancer agents with nontaxane skeleton as well as in identifying the clinical subsets responsive to paclitaxel-based therapy. [Cancer Res 2009;69(17):6906–14]