期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 43, 期 3, 页码 327-336出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2007.06.005
关键词
vincristine; cardiac myocytes; cell culture; hydrogen peroxide; oxidative stress; hypoxia; cardioprotection; signal transduction
资金
- NHLBI NIH HHS [P01 HL 68738] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL068738] Funding Source: NIH RePORTER
Vincristine is a chemotherapeutic agent that disrupts microtubules. We noted that paclitaxel (Taxol), which stabilizes microtubules, protected cultured adult mouse cardiac myocytes from oxidative stress induced by H2O2. We hypothesized that vincristine, which disrupts microtubules, should have the opposite effect. To our surprise, we found that pretreatment with concentrations of vincristine ranging from 30 to 120 mu mol/L for 60 min preserved myocyte viability and morphology after incubation with 30 mu mol/L of H2O2 for 35 min as measured by trypan blue exclusion. The cardioprotective effects of vincristine were also observed during prolonged hypoxia. With continuous exposure to vincristine, survival lasted for as long as 24 h, but longer periods of exposure up to 42 h resulted in extensive cell death. Despite microtubule disruption evidenced on deconvolution microscopy, vincristine activated a prosurvival pathway resulting in increased phosphorylation of Akt, ERK and GSK-3 and in reduced cytochrome C release into the cytosol. Pharmacological inhibitors of Akt and Erk attenuated the cardioprotective effect of vincristine. We conclude that short-term pretreatment with vincristine exerts dramatic protective effects in cultured adult mouse myocytes subjected to acute oxidative stress. Despite causing microtubule disruption, vincristine initiates a prosurvival signaling pathway. As vincristine and doxorubicin are often used in conjunction to treat patients, it is possible that vincristine could be used to modify the cardiotoxicity of doxorubicin. (c) 2007 Elsevier Inc. All rights reserved.
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