Doxorubicin causes transient activation of protein poly(ADP-ribosyl)ation in H9c2 cardiomyocytes

Abstract

Possible involvement of the system of protein poly(ADP-ribosyl)ation in the mechanisms of cardiotoxicity of doxorubicin, one of the most frequently used anticancer drug, was studied in cultures of cardiomyocytes H9c2. The treatment of H9c2 cells with doxorubicin (1 µM) led to a transient (after 6 h of incubation) increase in the nuclear level of poly(ADP-ribosyl)ated proteins. The observed data indirectly indicate the development of genotoxic stress in the doxorubicin-treated cells, probably caused by the stimulatory effects of doxorubicin and its metabolites on the production of reactive oxygen and nitrogen species.

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

“…Recently, we have reported that the increased PARylation level of FoxO3 play a crucial role in ISO-caused cardiac hypertrophy in vivo and in vitro 37 . Over-activation of PARP1 exerts a critical effect on the cardiac dysfunction in DOX-cardiomyopathy 44 . The PARylated protein levels were dramatically induced by DOX in the cardiomyocytes44, 45, 46, 47. Inhibition of PARP protects against DOX-induced myocardial apoptosis and heart injury44, 47.…”

“…In the heart, activation of PARP1 contributes to the various cardiovascular diseases, which were accompanied by the increased PARylated-target proteins, NAD repletion and sirtuins inactivation44, 45, 46, 47, 52, 53, 54 Previous papers from our laboratory demonstrated that PARP1 is strongly activated by AngII or isoproterenol (ISO), meanwhile its novel inhibitors (salvianolic acid B and AG-690/11026014) protect the myocardium from Ang II-stressed hypertrophy in vitro and in vivo 55, 56, 57, 58. Recently, we have reported that the increased PARylation level of FoxO3 play a crucial role in ISO-caused cardiac hypertrophy in vivo and in vitro 37 . Over-activation of PARP1 exerts a critical effect on the cardiac dysfunction in DOX-cardiomyopathy 44 .…”

“…PARP1 is an attractive antitumor target in clinical trials and its inhibitors including INO-1001, ABT888, PJ34 and AZD2281, were widely used in combination with chemotherapeutic agents including DOX39, 40, 41, 42, 43. DOX treatment caused a remarkable induction of PARylated protein levels in the cardiomyocytes44, 45, 46. Over-activation of PARP1 contributed to the cardiac dysfunction in DOX-cardiomyopathy 44 , while inhibition of PARP1 protects against DOX-induced myocardial apoptosis and heart injury44, 47.…”