Olaquindox-induced apoptosis is suppressed through p38 MAPK and ROS-mediated JNK pathways in HepG2 cells

Abstract

We investigated mitogen-activated protein kinase (MAPK) pathways as well as reactive oxygen species (ROS) in olaquindox-induced apoptosis. Exposure of HepG2 cells to olaquindox resulted in the phosphorylation of p38 MAPK and c-Jun N-terminal kinases (JNK). To confirm the role of p38 MAPK and JNK, HepG2 cells were pretreated with MAPKs-specific inhibitors prior to olaquindox treatment. Olaquindox-induced apoptosis was significantly potentiated by the JNK inhibitor (SP600125) or the p38 MAPK inhibitor (SB203580). Furthermore, we observed that olaquindox treatment led to ROS generation and that olaquindox-induced apoptosis and ROS generation were both significantly reduced by the antioxidants, superoxide dismutase and catalase. In addition, the levels of phosphorylation of JNK, but not p38 MAPK, were significantly suppressed after pretreatment of the antioxidants, while inhibition of the activations of JNK or p38 MAPK had no effect on ROS generation. This result suggested that ROS may be the upstream mediator for the activation of JNK. Conclusively, our results suggested that apoptosis in response to olaquindox treatment in HepG2 cells might be suppressed through p38 MAPK and ROS-JNK pathways.

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

“…CAT partially reversed the ROS levels and partially alleviated DNA damage when HeLa cells, HepG2 cells, primary pig hepatocytes, and primary chicken embryo hepatocytes were incubated with MEQ (50 lg/mL) and CAT (50 U), suggesting that CAT could protect against apoptosis, cellular DNA damage induced by MEQ in part, via ROS down-regulation . In addition, the combination of SOD (500 U/mL) and CAT (500 U/mL) significantly decreased ROS production and the levels of phosphorylation of JNK induced by OLA (800 lg/mL) in HepG2 cells, indicating that SOD and CAT might inhibit cell apoptosis via ROS-JNK pathway (Zhao et al, 2013). Zhang et al revealed that vitamin C (100 lM) increased the survival rates of HepG2 cells of QCT groups (80 and 320 lM), whereas vitamin E (10 and 100 lM) could not (Zhang et al, 2014).…”

“…Li et al revealed that OLA (1, 2, 3 and 4 lM/mL) increased the apoptosis rate of renal tubular epithelial cells (HK-2 cells) followed by ROS generation, suggesting that OLA might cause renal toxicity through the apoptosis-associated toxicity pathway via oxidative stress . After the exposure of HepG2 cells to OLA (800 lg/mL) for 24 or 48 h, OLA led to significant apoptosis (Zhang et al, 2011;Zhao et al, 2013;Zou et al, 2011). Similarly, when HepG2 cells were incubated with QCT, DQCT and MQCA for 24 h, QCT (10, 20, 30 and 40 lM) resulted in significant apoptosis whereas 80 lM of DQCT and MQCA did not cause apoptosis, indicating that the N!O group plays important roles in the toxicity of QdNOs (Zhang et al, 2015).…”

“…OLA treatment (200, 400 and 800 lg/mL) for 24 h caused a dose-dependent increase in ROS level in HepG2 cells (Zhao et al, 2015). Furthermore, Zhao et al documented that ROS generation induced by OLA increased in a time-dependent manner from 4 h to 24 h when HepG2 cells were treated with 800 lg/mL OLA for a number of time points (0, 0.5, 1, 2, 4, 6, 12 and 24 h) (Zhao et al, 2013). After the exposure of HepG2 cells to OLA (800 lg/mL) for 24 h, OLA significantly increased the ROS generation compared to control cells (Zhang et al, 2011).…”

“…Zhao et al documented that OLA induced the JNK pathway with ROS production when HepG2 cells were exposed to OLA (200, 400 and 800 lg/mL) for 24 cells (Zhao et al, 2015). Additionally, 400 lg/mL OLA treatment in HepG2 cells resulted in the phosphorylation of p38 MAPK and JNK along with ROS generation (Zhao et al, 2013). Zhang et al documented that after HepG2 cells were exposed to QCT (2.5-12.5 lg/mL), QCT significantly increased phospho-p38 and phospho-JNK proteins .…”

“…As already known, ROS generation and oxidative stress resulted from the reduction of QdNOs, which might result in wide damage such as apoptosis, and DNA, lipid and protein damage (Azqueta et al, 2007;Chowdhury et al, 2004;Wang et al, 2016a) in vivo or in vitro. During the past more than 10 years, there has been considerable focus on the potential of QdNOs to induce (Dai et al, 2015;Huang et al, 2010b;Li et al, 2015;Liu et al, 2012;Wang et al, 2015bWang et al, , 2016bWang et al, , 2015cYang et al, 2013bZhang et al, 2011Zhang et al, , 2013Zhang et al, , 2014Zhang et al, , 2015Zhao et al, 2013Zhao et al, , 2015Zou et al, 2009Zou et al, , 2011. Oxidative stress was also observed in rats Ihsan et al, 2010Ihsan et al, , 2011Wang et al, 2011c;Yu et al, 2014Yu et al, , 2013 and mice Zhao et al, 2011).…”