Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes.
- Author:
Seon Young KIM
1
;
Sang Jin KIM
;
Byoung Joo KIM
;
So Young RAH
;
Sung Mo CHUNG
;
Mie Jae IM
;
Uh Hyun KIM
Author Information
1. Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea. uhkim@chonbuk.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
apoptosis;
calcium signaling;
doxorubicin;
myocytes, cardiac;
reactive oxygen species
- MeSH:
Sarcoplasmic Reticulum/drug effects;
Ryanodine Receptor Calcium Release Channel/metabolism;
Reactive Oxygen Species/*chemical synthesis;
Rats, Sprague-Dawley;
Rats;
Myocytes, Cardiac/*drug effects;
Male;
Female;
Enzyme Activation/drug effects;
Doxorubicin/*pharmacology;
Cells, Cultured;
Caspase 3/metabolism;
Calcium Channel Blockers/pharmacology;
Calcium/*metabolism;
Antioxidants/pharmacology;
Antibiotics, Antineoplastic/pharmacology;
Animals
- From:Experimental & Molecular Medicine
2006;38(5):535-545
- CountryRepublic of Korea
- Language:English
-
Abstract:
Doxorubicin (DOX) is one of the most potent anticancer drugs and induces acute cardiac arrhythmias and chronic cumulative cardiomyopathy. Though DOX-induced cardiotoxicity is known to be caused mainly by ROS generation, a disturbance of Ca2+ homeostasis is also implicated one of the cardiotoxic mechanisms. In this study, a molecular basis of DOX-induced modulation of intracellular Ca2+ concentration ([Ca2+]i) was investigated. Treatment of adult rat cardiomyocytes with DOX increased [Ca2+]i irrespectively of extracellular Ca2+, indicating DOX-mediated Ca2+ release from intracellular Ca2+ stores. The DOX-induced Ca2+ increase was slowly processed and sustained. The Ca2+ increase was inhibited by pretreatment with a sarcoplasmic reticulum (SR) Ca2+ channel blocker, ryanodine or dantrolene, and an antioxidant, alpha-lipoic acid or alpha-tocopherol. DOX-induced ROS generation was observed immediately after DOX treatment and increased in a time-dependent manner. The ROS production was significantly reduced by the pretreatment of the SR Ca2+ channel blockers and the antioxidants. Moreover, DOX-mediated activation of caspase-3 was significantly inhibited by the Ca2+ channel blockers and a-lipoic acid but not a-tocopherol. In addition, cotreatment of ryanodine with alpha-lipoic acid resulted in further inhibition of the casapse-3 activity. These results demonstrate that DOX-mediated ROS opens ryanodine receptor, resulting in an increase in [Ca2+]i and that the increased [Ca2+]i induces ROS production. These observations also suggest that DOX/ROS-induced increase of [Ca2+]i plays a critical role in damage of cardiomyocytes.
