Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

Ming Huang Chen; Kun Chun Chiang; Chi Tung Cheng; Shih Chiang Huang; Yeng Yang Chen; Tsung Wen Chen; Ta Sen Yeh; Yi Yin Jan; Hsi Ming Wang; Jiang Jie Weng; Peter Mu Hsin Chang; Chun Yu Liu; Chung Pin Li; Yee Chao; Ming Han Chen; Chi Ying F. Huang; Chun Nan Yeh

doi:10.18632/oncotarget.1706

Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

Ming Huang Chen
, Kun Chun Chiang
, Chi Tung Cheng
, Shih Chiang Huang
, Yeng Yang Chen
, Tsung Wen Chen
, Ta Sen Yeh
, Yi Yin Jan
, Hsi Ming Wang
, Jiang Jie Weng
, Peter Mu Hsin Chang
, Chun Yu Liu
, Chung Pin Li
, Yee Chao
, Ming Han Chen
, Chi Ying F. Huang^*
, Chun Nan Yeh

^*Corresponding author for this work

National Yang Ming Chiao Tung University
Veterans General Hospital-Taipei
Chang Gung Memorial Hospital

Research output: Contribution to journal › Journal Article › peer-review

64 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2372-2389
Number of pages	18
Journal	Oncotarget
Volume	5
Issue number	9
DOIs	https://doi.org/10.18632/oncotarget.1706
State	Published - 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Heat-shock protein 90
NVP-AUY922
NVP-BEZ235
Phosphatase and tensin homolog

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10.18632/oncotarget.1706

Cite this

Chen, M. H., Chiang, K. C., Cheng, C. T., Huang, S. C., Chen, Y. Y., Chen, T. W., Yeh, T. S., Jan, Y. Y., Wang, H. M., Weng, J. J., Chang, P. M. H., Liu, C. Y., Li, C. P., Chao, Y., Chen, M. H., Huang, C. Y. F., & Yeh, C. N. (2014). Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. Oncotarget, 5(9), 2372-2389. https://doi.org/10.18632/oncotarget.1706

@article{f7f32232a36a4b389306307e2297782d,

title = "Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma",

abstract = "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.",

keywords = "Heat-shock protein 90, NVP-AUY922, NVP-BEZ235, Phosphatase and tensin homolog",

author = "Chen, \{Ming Huang\} and Chiang, \{Kun Chun\} and Cheng, \{Chi Tung\} and Huang, \{Shih Chiang\} and Chen, \{Yeng Yang\} and Chen, \{Tsung Wen\} and Yeh, \{Ta Sen\} and Jan, \{Yi Yin\} and Wang, \{Hsi Ming\} and Weng, \{Jiang Jie\} and Chang, \{Peter Mu Hsin\} and Liu, \{Chun Yu\} and Li, \{Chung Pin\} and Yee Chao and Chen, \{Ming Han\} and Huang, \{Chi Ying F.\} and Yeh, \{Chun Nan\}",

year = "2014",

doi = "10.18632/oncotarget.1706",

language = "英语",

volume = "5",

pages = "2372--2389",

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Chen, MH, Chiang, KC, Cheng, CT, Huang, SC, Chen, YY, Chen, TW, Yeh, TS, Jan, YY, Wang, HM, Weng, JJ, Chang, PMH, Liu, CY, Li, CP, Chao, Y, Chen, MH, Huang, CYF & Yeh, CN 2014, 'Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma', Oncotarget, vol. 5, no. 9, pp. 2372-2389. https://doi.org/10.18632/oncotarget.1706

TY - JOUR

T1 - Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

AU - Chen, Ming Huang

AU - Chiang, Kun Chun

AU - Cheng, Chi Tung

AU - Huang, Shih Chiang

AU - Chen, Yeng Yang

AU - Chen, Tsung Wen

AU - Yeh, Ta Sen

AU - Jan, Yi Yin

AU - Wang, Hsi Ming

AU - Weng, Jiang Jie

AU - Chang, Peter Mu Hsin

AU - Liu, Chun Yu

AU - Li, Chung Pin

AU - Chao, Yee

AU - Chen, Ming Han

AU - Huang, Chi Ying F.

AU - Yeh, Chun Nan

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Heat-shock protein 90

KW - NVP-AUY922

KW - NVP-BEZ235

KW - Phosphatase and tensin homolog

UR - https://www.scopus.com/pages/publications/84901227832

U2 - 10.18632/oncotarget.1706

DO - 10.18632/oncotarget.1706

M3 - 文章

C2 - 24796583

AN - SCOPUS:84901227832

SN - 1949-2553

VL - 5

SP - 2372

EP - 2389

JO - Oncotarget

JF - Oncotarget

IS - 9

ER -

Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma

Abstract

UN SDGs

Keywords

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