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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

Jun-Mei Yi, Xia-Juan Huan, Shan-Shan Song, Hu Zhou, Ying-Qing Wang and Ze-Hong Miao
Jun-Mei Yi
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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Xia-Juan Huan
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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Shan-Shan Song
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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Hu Zhou
2CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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Ying-Qing Wang
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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  • For correspondence: zhmiao@simm.ac.cn yqwang@simm.ac.cn
Ze-Hong Miao
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
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  • For correspondence: zhmiao@simm.ac.cn yqwang@simm.ac.cn
DOI: 10.1158/1535-7163.MCT-15-0753 Published July 2016
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Abstract

Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. Mol Cancer Ther; 15(7); 1495–503. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received September 11, 2015.
  • Revision received March 16, 2016.
  • Accepted March 19, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 15 (7)
July 2016
Volume 15, Issue 7
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Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44
Jun-Mei Yi, Xia-Juan Huan, Shan-Shan Song, Hu Zhou, Ying-Qing Wang and Ze-Hong Miao
Mol Cancer Ther July 1 2016 (15) (7) 1495-1503; DOI: 10.1158/1535-7163.MCT-15-0753

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Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44
Jun-Mei Yi, Xia-Juan Huan, Shan-Shan Song, Hu Zhou, Ying-Qing Wang and Ze-Hong Miao
Mol Cancer Ther July 1 2016 (15) (7) 1495-1503; DOI: 10.1158/1535-7163.MCT-15-0753
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