Activation of AMP-Activated Protein Kinase Contributes to Doxorubicin-Induced Cell Death and Apoptosis in Cultured Myocardial H9c2 Cells

Abstract

Despite its potent antitumor effect, clinical use of Doxorubicin is limited because of serious side effects including myocardial toxicity. Understanding the cellular mechanism involved in this process in a better manner is beneficial for optimizing Doxorubicin treatment. In the current study, the authors focus on the AMP-activated protein kinase (AMPK) in the said process. In this study, the authors discovered for the first time that Doxorubicin induces AMPK activation in cultured rat embryonic ventricular myocardial H9c2 cells. Reactive oxygen species (ROS)-dependent LKB1 activation serves as the upstream signal for AMPK activation by Doxorubicin. Evidence in support of the activation of AMPK contributing to Doxorubicin-induced H9c2 cell death/apoptosis--probably by modulating multiple downstream signal targets, including regulating JNK, p53, and inhibiting mTORC1--is provided in this article.

Inhibition of AMP-activated Protein Kinase α (AMPKα) by Doxorubicin Accentuates Genotoxic Stress and Cell Death in Mouse Embryonic Fibroblasts and Cardiomyocytes

“…Notably, we observed that doxorubicin might activates AMPK at initial stage (Ͻ4 h), but it did not induce cell apoptosis under short time treatment under our current conditions (Fig. 7, A and B), similar results were reported by other groups (43,44), which might be due to a transient increase in reactive oxygen species levels after adding doxorubicin (44). But the detailed mechanism of this transient activation of AMPK by doxorubicin is unknown, which warrants further investigation.…”

“…However, the role of AMPK in doxorubicin-induced apoptosis is a matter of debate. For example, Chen et al (44) and Ji et al (43) have described that doxorubicin-induced early AMPK (Ͻ6 h) contributes to cellular death (Ͼ16 h) in cultured H9C2 cells or in cancer cell lines. Whether or not doxorubicin-induced AMPK activation at early stage (Ͻ6 h) is responsible for late stage apoptosis is unknown because prolonged incubation of doxorubicin inhibits AMPK.…”

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

“…Detailed procedures can be found in other studies. 37,38 Briefly, the cells were lysed and the cell lysates were overlaid and incubated in microtiter plate modules coated with anti-Histone antibody. Samples were then incubated with anti-DNA peroxidase followed by color development with ABTS substrate.…”

AMP-activated Protein Kinase α2 and E2F1 Transcription Factor Mediate Doxorubicin-induced Cytotoxicity by Forming a Positive Signal Loop in Mouse Embryonic Fibroblasts and Non-carcinoma Cells

“…In contrast to the well established role of AMPK in metabolic regulation, there is no consensus on its role or the underlying mechanism under genotoxic stress. Some reports have demonstrated that AMPK is activated in H9c2 (14) and cancer cell lines (15) by doxorubicin. In contrast, AMPK is inhibited by long term treatment of doxorubicin in mouse embryonic fibroblasts (MEFs) (16).…”