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

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...

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Bibliographic Details
Published in:Clinical cancer research 2005-08, Vol.11 (16), p.6002-6011
Main Authors: WONG, Vincent K. W, CHIU, Pauline, CHUNG, Stephen S. M, CHOW, Larry M. C, ZHAO, Yun-Zhe, YANG, Burton B, KO, Ben C. B
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Apoptosis - drug effects
Binding Sites
Binding, Competitive - drug effects
Biological and medical sciences
Blotting, Western
Cell Cycle Proteins - metabolism
Cell Division - drug effects
Cell Line
Cell Line, Tumor
Cell Survival - drug effects
Colchicine - pharmacology
Diterpenes - chemistry
Diterpenes - pharmacology
Diterpenes - therapeutic use
Dose-Response Relationship, Drug
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm - drug effects
Drugs, Chinese Herbal
G2 Phase - drug effects
HeLa Cells
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Microscopy, Fluorescence
Microtubule
Microtubules - metabolism
Molecular Structure
Multidrug resistant
Nude mice
Pharmacology. Drug treatments
Pseudolaric acid B
Time Factors
Treatment Outcome
Tubulin
Tubulin - metabolism
Xenograft Model Antitumor Assays - methods
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Summary: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 G 2 -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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-05-0209