Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma
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Ming-Huang Chen1, 2, Kun-Chun Chiang3, Chi-Tung Cheng4, Shih-Chiang Huang 5, Yeng-Yang Chen6, Tsung-Wen Chen4, Ta-Sen Yeh4, Yi-Yin Jan4, Hsi-Ming Wang2, Jiang-Jie Weng2, Peter Mu-Hsin Chang1, 2, Chun-Yu Liu1, 2, Chung-Pin Li1,7, Yee Chao1, 8, Ming-Han Chen1, Chi-Ying F. Huang9, Chun-Nan Yeh4
1 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
2 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
3 General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan
4 Department of Surgery, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University, Taoyuan County, Taiwan
5Department of Pathology, Chang Gung Memorial Hospital and University, Taoyuan County, Taiwan
6 Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
7 Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
8 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
9 Institute of Clinical Medicine, Institute of Biopharmaceutical Sciences, and Genome Research Center, Yang-Ming University, Taipei, Taiwan
Chi-Ying F. Huang, e-mail: [email protected]
Chun-Nan Yeh, e-mail: [email protected]
Keywords: NVP-AUY922, NVP-BEZ235, heat-shock protein 90, phosphatase and tensin homolog
Received: December 16, 2013 Accepted: March 21, 2014 Published: March 26, 2014
The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination.
Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.
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