The Protective Effect of INH₂BP, a Novel PARP Inhibitor 5-Iodo-6-Amino-1,2-Benzopyrone, Against Hydrogen Peroxide-Induced Apoptosis Through ERK and p38 MAPK in H9c2 Cells

Abstract

INH₂BP (5-iodo-6-amino-1,2-benzopyrone), a poly-ADP ribose polymerase inhibitor, has been shown to possess anti-cancer, anti-viral, and anti-inflammation properties. The aim of this study was to investigate the protective effect of INH₂BP against oxidative stress-induced apoptosis in H9c2 cardiomyoblast cells. While the treatment of H9c2 cardiomyoblasts cells with hydrogen peroxide (H₂O₂) caused a loss of cell viability and an increase in the number of apoptotic cells, INH₂BP significantly protected the cells against H₂O₂-induced cell death without any cytotoxicity. Our data also shows that INH₂BP significantly scavenged intracellular reactive oxygen species (ROS), and markedly enhanced the expression of antioxidant enzymes such as Mn-SOD (superoxide) and Cu/Zn-SOD, and heme oxygenase-1, which was accompanied by the concomitant activation of extracellular regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) phosphorylation in H9c2 cells. The effects of INH₂BP on ERK1/2 and p38 MAPK phosphorylation were abrogated by PD98059, an ERK1/2 inhibitor, and SB203580, a p38 inhibitor. In addition, inhibition of ERK1/2 and p38 MAPK by these inhibitors significantly attenuated INH₂BP-mediated H9c2 viability as well as cleaved caspases-3, Bax, and Bcl-2 activation. Taken together, these results demonstrate that INH₂BP prevents H₂O₂-induced apoptosis in H9c2 cells by reducing the production of intracellular ROS, regulating apoptotic-related proteins, and the activation of the ERK1/2 and p38 MAPK.

Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses

“…In HeLa cells, extensive activation of PARylation by MNNG specifically decreased phosphorylation of ERK1/2, which ultimately induced cell death in an ERK-dependent manner 133 . A similar effect was observed in H 2 O 2 -induced ADP-ribosylation and apoptosis in cardiomyoblasts, which correlated with a reduction in both ERK and p38 phosphorylation 160 . PARP inhibitor administration (INH 2 BP) increased phosphorylation of ERK and p38 and cell viability, led to a downregulation of ROS and pro-apoptotic factors and increased levels of anti-apoptotic proteins 160 .…”

“…A similar effect was observed in H 2 O 2 -induced ADP-ribosylation and apoptosis in cardiomyoblasts, which correlated with a reduction in both ERK and p38 phosphorylation 160 . PARP inhibitor administration (INH 2 BP) increased phosphorylation of ERK and p38 and cell viability, led to a downregulation of ROS and pro-apoptotic factors and increased levels of anti-apoptotic proteins 160 . Specific ERK and p38 inhibitors individually and in combination counteracted the pro-survival effect of INH 2 BP 160 , suggesting that the pro-survival effect of this PARP inhibitor could be ascribed to both MAP kinases.…”

“…PARP inhibitor administration (INH 2 BP) increased phosphorylation of ERK and p38 and cell viability, led to a downregulation of ROS and pro-apoptotic factors and increased levels of anti-apoptotic proteins 160 . Specific ERK and p38 inhibitors individually and in combination counteracted the pro-survival effect of INH 2 BP 160 , suggesting that the pro-survival effect of this PARP inhibitor could be ascribed to both MAP kinases. Of note, the ERK pathway had already been implicated in cardiac protection, while the pro-apoptotic or protective consequences of p38 signaling for the heart continue to be controversially discussed 161 .…”

Proliferation of Lung Epithelial Cells Is Regulated by the Mechanisms of Autophagy Upon Exposure of Soots

“…It is clearly seen that H 2 O 2 completed the autophagy and initiated the apoptotic events; however, soot alone did not induce autophagy. It is already known that H 2 O 2 induces apoptosis via cleaved caspase-3 induction ( Back et al, 2015 ; Li et al, 2015 ). In this study, soot inhibited H 2 O 2 -induced apoptosis and also inhibited cleaved caspase-3 expression and nuclear localization, suggesting its role at the transcription factor level.…”

Proliferation of lung epithelial cells is regulated by the mechanisms of autophagy upon exposure of soots

“…It is clearly seen that, H 2 O 2 completed the autophagy and initiated the apoptotic events however soot alone did not induce autophagy. It is already known that, H 2 O 2 induces apoptosis via way of cleaved caspase-3 induction (Li et al 2015; Back et al 2015). In this study, soot has inhibited H 2 O 2 induced apoptosis and also inhibited cleaved caspase-3 expression and nuclear localization suggesting its role at transcription factor level.…”