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The Taccalonolides: Microtubule Stabilizers That Circumvent Clinically Relevant Taxane Resistance Mechanisms

¹ Department of Physiology and Medicine, Southwest Foundation for Biomedical Research; ² Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas; ³ Division of Hematology-Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; ⁴ Nuclear Magnetic Resonance Center, Washington State University, Pullman, Washington; and ⁵ Department of Medicine and Cancer Center, University of Illinois at Chicago Cancer Center, Chicago, Illinois

Requests for reprints: Susan L. Mooberry, Department of Pharmacology, University of Texas Health Science Center, Mail Code 7764, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Phone: 210-567-4788; E-mail: Mooberry{at}uthscsa.edu.

Key Words: microtubule stabilizers • drug resistance • P-glycoprotein • multidrug-resistant protein 7 • βIII-tubulin

The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein (Pgp), multidrug resistance protein 7 (MRP7), and the βIII isotype of tubulin. The ability of four taccalonolides, A, E, B, and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B, and N were effective in vitro against cell lines that overexpress Pgp and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel-resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the βIII isotype of tubulin was generated to evaluate the effect of βIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the βIII-tubulin–overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine. In striking contrast, the βIII-tubulin–overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential. [Cancer Res 2008;68(21):8881–8]