摘要

Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in nonsmall 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- a-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-a. 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.
原文英語
頁(從 - 到)23857-23873
頁數17
期刊Oncotarget
6
發行號27
DOIs
出版狀態已發佈 - 2015

指紋

Lovastatin
Cholangiocarcinoma
Heterografts
In Vitro Techniques
gefitinib
Proteasome Inhibitors
Cell Cycle Checkpoints
Immunoblotting
Non-Small Cell Lung Carcinoma
Flow Cytometry
Cell Death
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Oncology

引用此文

@article{175c6aa28428430e96adbb55280c5627,
title = "Lovastatin overcomes gefitinib resistance through TNF-a signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo",
abstract = "Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in nonsmall 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- a-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-a. 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.",
keywords = "Cholangiocarcinomas, Combination therapy, Gefitinib, Lovastatin",
author = "Yang, {Sheng Huei} and Lin, {Hung Yun} and Chang, {Vincent H S} and Chen, {Chien Chung} and Liu, {Yun Ru} and Jinghan Wang and Keqiang Zhang and Xiaoqing Jiang and Yun Yen",
year = "2015",
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issn = "1949-2553",
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TY - JOUR

T1 - Lovastatin overcomes gefitinib resistance through TNF-a signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo

AU - Yang, Sheng Huei

AU - Lin, Hung Yun

AU - Chang, Vincent H S

AU - Chen, Chien Chung

AU - Liu, Yun Ru

AU - Wang, Jinghan

AU - Zhang, Keqiang

AU - Jiang, Xiaoqing

AU - Yen, Yun

PY - 2015

Y1 - 2015

N2 - Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in nonsmall 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- a-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-a. 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.

AB - Gefitinib resistance has been shown to complicate cancer therapy. Lovastatin is a proteasome inhibitor that enhances gefitinib-induced antiproliferation in nonsmall 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- a-induced cell death in vitro. In addition, the combination of lovastatin with gefitinib enhanced accumulation of TNF-a. 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.

KW - Cholangiocarcinomas

KW - Combination therapy

KW - Gefitinib

KW - Lovastatin

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