Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro.

Abstract

The anthracycline antibiotic doxorubicin produces a characteristic myopathy in cardiac muscle that limits its use in cancer therapy. We have shown in cultured neonatal rat cardiac muscle cells that doxorubicin treatment resulted in a rapid, selective decrease in the expression of muscle-specific genes, which preceded other changes characteristic of doxorubicin cardiomyopathy. Doxorubicin selectively and dramatically decreased the levels of mRNA for the sarcomeric genes, a-actin, troponin I, and myosin light chain 2, as well as the muscle-specific, but nonsarcomeric M isoform of creatine kinase. However, doxorubicin did not affect nonmuscle gene transcripts (pyruvate kinase, ferritin heavy chain, and 3-actin). Actinomycin D, an inhibitor of DNA-dependent RNA polymerase, did not show a similar selective decrease of muscle-specific mRNAs but, rather, produced a nonspecific, dose-dependent decrease of muscle and nonmuscle transcripts. The doxorubicin effect on muscle gene expression was limited to cardiac muscle; cultured skeletal myocytes were resistant to the effects of doxorubicin at 100-fold greater doses than those causing changes in mRNA levels in cardiac muscle cells. These effects of doxorubicin were reproduced in vivo; rats ih'ected with doxorubicin showed a dose-dependent decrease in the levels of mRNAs for a-actin, troponin I, myosin light chain 2, and M isoform of creatine kinase in cardiac but not skeletal muscle. These selective changes in gene expression in cardiocyte cultures and cardiac muscle precede classical ultrastructural changes and may explain the myofibrillar loss that characterizes doxorubicin cardiac injury.

Mitochondrial DNA determines the cellular response to cancer therapeutic agents

“…However, as cumulative dose increases, the incidence of congestive heart failure increases rapidly (Von Ho et al, 1979;Shan et al, 1996). Recent evidence suggests that anthracycline therapy also leads to arrythmias, pericarditis-myocarditis syndrome, ventricular dysfunction and cardiomyopathies, sometimes 2 ± 15 years after treatment has ceased (Ito et al, 1990;Von Ho et al, 1979;Shan, 1996). Studies reported in this paper suggest that adriamycin-induced mutation in mitDNA may accumulate and contribute to cardiac pathology observed in cancer patients.…”

“…Adriamycin, a member of the anthracycline class of drugs is one of the most e ective anticancer agents and is widely used in therapy of childhood leukemias, lymphomas and solid tumors (Ito et al, 1990;Von Ho et al, 1979). However, as cumulative dose increases, the incidence of congestive heart failure increases rapidly (Von Ho et al, 1979;Shan et al, 1996).…”

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

“…HSP20, HSP21, HSP2, HSP70) can be either cardioprotective or detrimental in this setting (Liu et al, 2007; Vedam et al, 2010; Wang et al, 2016). Other putative mechanisms include damage to nuclear DNA, disruption of sarcomeric protein synthesis (Ito et al, 1990), accumulation of the tumour suppressor protein, p53 (Yoshida et al, 2009) and a disturbance of energy metabolism (Tokarska‐Schlattner et al, 2006). In mitochondria, increased ROS leads to Ca 2+ overload, which triggers mitochondrial permeability transition, resulting in loss of membrane potential, swelling and outer membrane rupture, and consequent activation of caspases, release of cytochrome c and apoptosis.…”

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

“…Studies have shown that doxorubicin decreases the expression of -sarcomeric actin, cardiac troponin I (cTnI), and myosin light chain 2 (MLC 2) (Ito et al, 1990). Doxorubicin treatment decreases cardiac troponins in left ventricular tissues of mice and in cultured rat neonatal cardiomyocytes (Bian et al, 2009).…”

“…(3) inhibition of cardiac specific muscle gene transcription and translation, in combination with an increase in myofibril protein degradation, leading to loss of myofibrils (Lewis and Gonzalez, 1987;Ito et al, 1990;Kurabayashi et al, 1994;Toyoda et al, 1998;d'Anglemont de Tassigny et al, 2004;Lim et al, 2004b), and (4) disturbance of intracellular calcium homeostasis (De Beer et al, 2001;Wallace, 2003). The mechanism of doxorubicin-induced free radical generation and oxidative stress has been reviewed in other chapters of this book as well as comprehensive reviews in the field (Singal et al, 2000;Berthiaume and Wallace, 2007;Simunek et al, 2009).…”