Lovastatin overcomes gefitinib resistance through TNF-&#x03B1; signaling in human cholangiocarcinomas with different LKB1 statuses  in vitro  and  in vivo

Sheng-Huei Yang; Hung-Yun Lin; Vincent H.S. Chang; Chien-Chung Chen; Yun-Ru Liu; Jinghan Wang; Keqiang Zhang; Xiaoqing Jiang; Yun Yen

doi:10.18632/oncotarget.4408

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Research Papers:

Lovastatin overcomes gefitinib resistance through TNF-α signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo

Sheng-Huei Yang, Hung-Yun Lin, Vincent H.S. Chang, Chien-Chung Chen, Yun-Ru Liu, Jinghan Wang, Keqiang Zhang, Xiaoqing Jiang _ and Yun Yen

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Oncotarget. 2015; 6:23857-23873. https://doi.org/10.18632/oncotarget.4408

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Abstract

Sheng-Huei Yang1, Hung-Yun Lin1,2, Vincent H.S. Chang3, Chien-Chung Chen4, Yun-Ru Liu5, Jinghan Wang6, Keqiang Zhang7, Xiaoqing Jiang6, Yun Yen1

1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

2Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

3Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan

4Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan

5Office of Human Research, Taipei Medical University, Taipei, Taiwan

6The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China

7Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Center, Duarte, California, USA

Correspondence to:

Yun Yen, e-mail: [email protected]

Keywords: cholangiocarcinomas, combination therapy, lovastatin, gefitinib

Received: January 29, 2015 Accepted: June 12, 2015 Published: June 23, 2015

ABSTRACT

Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in non-small cell lung cancer. The objective of this study is to investigate the mechanism of lovastatin-induced antiproliferation in gefitinib-resistant human cholangiocarcinoma.

Two gefitinib-resistant cholangiocarcinoma cell lines, SSP-25 and HuH-28, were used in this study to determine how to compensate gefitinib resistance. The combined effect of these two drugs was examined using the MTT assay, qPCR, immunoblotting, flow cytometry, and in vivo xenograft. Results indicated that lovastatin enhanced TNF-α-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-α. Furthermore, the treatment induced a synergistic cytotoxic effect and antiproliferation through apoptosis in SSP-25 cells and cell cycle arrest in HuH-28 cells. Reproductive results were also observed in in vivo xenografts. These observations suggest that the combination of gefitinib and lovastatin might have additive antiproliferative effects against gefitinib-resistant cholangiocarcinoma cells. Based on these observations, we concluded that the combination of gefitinib and lovastatin could be used to overcome gefitinib resistance in cholangiocarcinoma cells.

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Research Papers:

Lovastatin overcomes gefitinib resistance through TNF-α signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo

Abstract