title: Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction.
abstract: A combined treatment with conventional chemotherapies can enhance the effectiveness of chemotherapeutic agents against cancers. Here, we have shown that the naturally occurring triterpenoids synergistically enhance the response of cervical cancer cells to taxol. Of the triterpenoid compounds, pristimerin enhanced the anticancer effect of taxol with the highest efficiency by combination. Pristimerin synergizes with taxol to inhibit clonogenic survival and tumor growth in nude mice, and to enhance cell death in cervical cancer cells. A combined treatment with taxol and pristimerin induced cervical cancer cell death by increasing intracellular reactive oxygen species levels, upregulation of death receptor death receptor 5 (DR5), activation of Bax, and dissipation of mitochondrial membrane potential. Treatment with N-acetyl-L-cysteine, a thiol-containing antioxidant completely blocked combined treatment-induced Bax translocation as well as DR5 upregulation. Moreover, inhibition of Jun N-terminal kinase/c-Jun pathway attenuated cell death by blocking DR5 upregulation and Bax activation. These results indicate that the triterpenoid, pristimerin, synergistically enhances taxol response of cervical cancer cells through DR5 expression and Bax activation. Furthermore, the reactive oxygen species-dependent activation of the Jun N-terminal kinase/c-Jun pathway is required for the DR5 upregulation and Bax activation. The molecular mechanism revealed by this study may aid in the design of future combination cancer therapies against cells with intrinsically reduced sensitivity to taxol.
authors.affiliation: Department of Chemistry, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Da-Young
authors.initials: DY
authors.lastname: Eum
authors.forename: Joo-Yun
authors.initials: JY
authors.lastname: Byun
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Woo-Duck
authors.initials: WD
authors.lastname: Seo
authors.forename: Ki-Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014315:Triterpenes / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; C050414:celastrol; D017239:Paclitaxel