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Article: Pseudolaric acid B, a novel microtubule-destabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivo

TitlePseudolaric acid B, a novel microtubule-destabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivo
Authors
Issue Date2005
Citation
Clinical Cancer Research, 2005, v. 11 n. 16, p. 6002-6011 How to Cite?
AbstractPurpose: 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. © 2005 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/167950
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWong, VKWen_HK
dc.contributor.authorChiu, Pen_HK
dc.contributor.authorChung, SSMen_HK
dc.contributor.authorChow, LMCen_HK
dc.contributor.authorZhao, YZen_HK
dc.contributor.authorYang, BBen_HK
dc.contributor.authorKo, BCBen_HK
dc.date.accessioned2012-10-08T03:13:17Z-
dc.date.available2012-10-08T03:13:17Z-
dc.date.issued2005en_HK
dc.identifier.citationClinical Cancer Research, 2005, v. 11 n. 16, p. 6002-6011en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/167950-
dc.description.abstractPurpose: 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. © 2005 American Association for Cancer Research.en_HK
dc.languageengen_US
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subject.meshAnimalsen_US
dc.subject.meshAntineoplastic Agents - Chemistry - Pharmacology - Therapeutic Useen_US
dc.subject.meshApoptosis - Drug Effectsen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshBinding, Competitive - Drug Effectsen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCell Cycle Proteins - Metabolismen_US
dc.subject.meshCell Division - Drug Effectsen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshColchicine - Pharmacologyen_US
dc.subject.meshDiterpenes - Chemistry - Pharmacology - Therapeutic Useen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshDrug Resistance, Multiple - Drug Effectsen_US
dc.subject.meshDrug Resistance, Neoplasm - Drug Effectsen_US
dc.subject.meshDrugs, Chinese Herbalen_US
dc.subject.meshG2 Phase - Drug Effectsen_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshLiver Neoplasms - Drug Therapy - Metabolism - Pathologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Balb Cen_US
dc.subject.meshMice, Nudeen_US
dc.subject.meshMicroscopy, Fluorescenceen_US
dc.subject.meshMicrotubules - Metabolismen_US
dc.subject.meshMolecular Structureen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTreatment Outcomeen_US
dc.subject.meshTubulin - Metabolismen_US
dc.subject.meshXenograft Model Antitumor Assays - Methodsen_US
dc.titlePseudolaric acid B, a novel microtubule-destabilizing agent that circumvents multidrug resistance phenotype and exhibits antitumor activity in vivoen_HK
dc.typeArticleen_HK
dc.identifier.emailChiu, P: pchiu@hku.hken_HK
dc.identifier.emailChung, SSM: smchung@hkucc.hku.hken_HK
dc.identifier.authorityChiu, P=rp00680en_HK
dc.identifier.authorityChung, SSM=rp00376en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/1078-0432.CCR-05-0209en_HK
dc.identifier.pmid16115945-
dc.identifier.scopuseid_2-s2.0-23844557173en_HK
dc.identifier.hkuros113847-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-23844557173&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume11en_HK
dc.identifier.issue16en_HK
dc.identifier.spage6002en_HK
dc.identifier.epage6011en_HK
dc.identifier.isiWOS:000231320000048-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridWong, VKW=8541929000en_HK
dc.identifier.scopusauthoridChiu, P=11140148700en_HK
dc.identifier.scopusauthoridChung, SSM=14120761600en_HK
dc.identifier.scopusauthoridChow, LMC=7202533071en_HK
dc.identifier.scopusauthoridZhao, YZ=7406636675en_HK
dc.identifier.scopusauthoridYang, BB=7404471996en_HK
dc.identifier.scopusauthoridKo, BCB=7102833927en_HK

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