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Title: Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes

Abstract

Dasatinib, a multitargeted inhibitor of BCR–ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague–Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. Thesemore » results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity. -- Highlights: ►Dasatinib shows potential hepatotoxicity both in vitro and in vivo. ►Apoptosis plays a vital role in Dasatinib-induced hepatotoxicity. ►Dasatinib increases ROS and causes oxidative stress in hepatocytes. ►N-acetylcysteine protects hepatocytes against Dasatinib-induced injury.« less

Authors:
; ; ;  [1]; ; ;  [2];  [1];  [1];  [3];  [1];  [3]
  1. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058 (China)
  2. Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 (China)
  3. (China)
Publication Date:
OSTI Identifier:
22215338
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 261; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; ANTIOXIDANTS; APOPTOSIS; BIOLOGICAL STRESS; CHROMATIN; GLUTATHIONE; IN VITRO; IN VIVO; INJURIES; LABELLING; LACTATE DEHYDROGENASE; LIPIDS; LIVER CELLS; MITOCHONDRIA; MYELOID LEUKEMIA; OXIDATION; PHILADELPHIA CHROMOSOME; PHOSPHOTRANSFERASES; RATS; SUPEROXIDE DISMUTASE

Citation Formats

Xue, Tao, Luo, Peihua, Zhu, Hong, Zhao, Yuqin, Wu, Honghai, Gai, Renhua, Wu, Youping, Yang, Bo, Yang, Xiaochun, E-mail: yangxiaochun@zju.edu.cn, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, He, Qiaojun, E-mail: qiaojunhe@zju.edu.cn, and Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058. Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.04.010.
Xue, Tao, Luo, Peihua, Zhu, Hong, Zhao, Yuqin, Wu, Honghai, Gai, Renhua, Wu, Youping, Yang, Bo, Yang, Xiaochun, E-mail: yangxiaochun@zju.edu.cn, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, He, Qiaojun, E-mail: qiaojunhe@zju.edu.cn, & Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058. Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. United States. doi:10.1016/J.TAAP.2012.04.010.
Xue, Tao, Luo, Peihua, Zhu, Hong, Zhao, Yuqin, Wu, Honghai, Gai, Renhua, Wu, Youping, Yang, Bo, Yang, Xiaochun, E-mail: yangxiaochun@zju.edu.cn, Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, He, Qiaojun, E-mail: qiaojunhe@zju.edu.cn, and Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058. Fri . "Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes". United States. doi:10.1016/J.TAAP.2012.04.010.
@article{osti_22215338,
title = {Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes},
author = {Xue, Tao and Luo, Peihua and Zhu, Hong and Zhao, Yuqin and Wu, Honghai and Gai, Renhua and Wu, Youping and Yang, Bo and Yang, Xiaochun, E-mail: yangxiaochun@zju.edu.cn and Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058 and He, Qiaojun, E-mail: qiaojunhe@zju.edu.cn and Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058},
abstractNote = {Dasatinib, a multitargeted inhibitor of BCR–ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague–Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity. -- Highlights: ►Dasatinib shows potential hepatotoxicity both in vitro and in vivo. ►Apoptosis plays a vital role in Dasatinib-induced hepatotoxicity. ►Dasatinib increases ROS and causes oxidative stress in hepatocytes. ►N-acetylcysteine protects hepatocytes against Dasatinib-induced injury.},
doi = {10.1016/J.TAAP.2012.04.010},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 261,
place = {United States},
year = {2012},
month = {6}
}