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The Seco-Taxane IDN5390 Is Able to Target Class III ß-Tubulin and to Overcome Paclitaxel Resistance

¹ Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy; ² European Research Centre for Drug Discovery and Development, Università degli Studi di Siena; ³ Dipartimento Farmaco Chimico Tecnologico, University of Siena, Siena, Italy; ⁴ Dipartimento di Chimica delle Sostanze Naturali, University of Napoli Federico II, Napoli, Italy; and ⁵ Department of Oncology, Catholic University of the Sacred Heart, Campobasso, Italy

Requests for reprints: Cristiano Ferlini, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Largo A. Gemelli, 8- 00168, Rome, Italy. Phone: 6-355-08736; Fax: 6-355-08736/06-305-1160; E-mail: cferlini{at}rm.unicatt.it.

A prominent mechanism of drug resistance to taxanes is the overexpression of class III ß-tubulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III ß-tubulin. Moreover, the combined treatment paclitaxel/IDN5390 yielded a strong synergism, which was also evident in cell-free tubulin polymerization assays. In the presence of an anti-class III ß-tubulin as a blocking antibody, tubulin polymerization induced by paclitaxel and IDN5390 was enhanced and not affected, respectively, whereas synergism was abolished, thereby indicating that IDN5390 activity is not modulated by class III ß-tubulin levels. Such properties can be explained by taking into consideration the composition of class III ß-tubulin paclitaxel binding site; in fact, Ser²⁷⁷ interacting with paclitaxel C group in class I is replaced by an Arginine in class III. IDN5390 that has an open and flexible C ring and an acidic -unsaturated enol-keton moiety better fits with class III ß-tubulin than paclitaxel at the binding site. Taking altogether, these findings indicate that the concomitant treatment IDN5390/paclitaxel is able to successfully target class I and III ß-tubulin and the combined use of two taxanes with diverse spectrum activity against tubulin isotypes could represent a novel approach to overcome paclitaxel resistance.

Key Words: paclitaxel • paclitaxel binding site • drug resistance • ß-tubulin isotypes

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