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Pseudolaric Acid B, a Novel Microtubule-Destabilizing Agent That Circumvents Multidrug Resistance Phenotype and Exhibits Antitumor Activity In vivo

Authors' Affiliations: ¹ Department of Chemistry, ² Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, and ³ Institute of Molecular Biology, The University of Hong Kong; ⁴ Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China; and ⁵ Sunnybrook and Women's College Health Sciences Centre and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Ben C.B. Ko, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region, China. Phone: 852-2299-0784; Fax: 852-2817-1006; E-mail: cbko{at}hkucc.hku.hk.

Purpose: Pseudolaric acid B (PAB) is the major bioactive constituent in the root bark of Pseudolarix kaempferi that has been used as an antifungal remedy in traditional Chinese medicine. Previous studies showed that PAB exhibited substantial cytotoxicity. The aims of this study were to elucidate the molecular target of PAB, to examine its mechanism of action, and to evaluate the efficacy of this compound in vivo.

Experimental Design: The effect of PAB on cell growth inhibition toward a panel of cancer cell lines was assayed. Cell cycle analysis, Western blotting, immunocytochemistry, and apoptosis analysis were carried out to examine the mechanism of action. Tubulin polymerization assays were conducted to examine the interaction between PAB and tubulin. A P-glycoprotein–overexpressing cell line was used to evaluate the efficacy of PAB toward multidrug-resistant phenotypes. In vivo efficacy of PAB was evaluated by the murine xenograft model.

Results: PAB induces cell cycle arrest at G₂-M transition, leading to apoptosis. The drug disrupts cellular microtubule networks and inhibits the formation of mitotic spindles. Polymerization of purified bovine brain tubulin was dose-dependently inhibited by PAB. Furthermore, PAB circumvents the multidrug resistance mechanism, displaying notable potency also in P-glycoprotein–overexpressing cells. Finally, we showed that PAB is effective in inhibiting tumor growth in vivo.

Conclusions: We identified the microtubules as the molecular target of PAB. Furthermore, we showed that PAB circumvents P-glycoprotein overexpression-induced drug resistance and is effective in inhibiting tumor growth in vivo. Our work will facilitate the future development of PAB as a cancer therapeutic.

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				Y.-G. Tong, X.-W. Zhang, M.-Y. Geng, J.-M. Yue, X.-L. Xin, F. Tian, X. Shen, L.-J. Tong, M.-H. Li, C. Zhang, et al. Pseudolarix Acid B, a New Tubulin-Binding Agent, Inhibits Angiogenesis by Interacting with a Novel Binding Site on Tubulin Mol. Pharmacol., April 1, 2006; 69(4): 1226 - 1233. [Abstract] [Full Text] [PDF]