Investigation of quinocetone-induced mitochondrial damage and apoptosis in HepG2 cells and compared with its metabolites

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

“…Treatment with OLA (200, 400 and 800 lg/mL) for 24 h caused a dose-dependent progressive increase in the population of HepG2 cells in the S phase and a dramatic decrease in the percentage of cells in G0/G1 phase, but had no pronounced effects on the G2/M phase, indicating that OLA inhibited HepG2 cell proliferation as a result of S phase arrest (Zou et al, 2011). Similarly, a significant increase in the percentage of cells in S phase was observed in HepG2 cells treated with QCT (20 and 40 lM) for 24 h, suggesting that QCT induced apoptosis via cell cycle arrest (Zhang et al, 2015). It was revealed that GADD45GIP1 gene encodes a nuclear-localized protein that may be induced by p53 and regulates the cell cycle by inhibiting G1 to S phase progression (Nakayama et al, 2007).…”

“…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).…”

“…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).…”

“…Bcl-2 and Bax, which belong to the Bcl-2 family, are major regulators of mitochondrial integrity and mitochondria-initiated Cyt c release and caspase activation (Lee et al, 2011a). It was revealed that QCT (30 lM) significantly increased the caspase-8 proteolytic activities, and QCT (15 and 30 lM) resulted in significant increases in caspase-9 activities, whereas the caspase-8 and caspase-9 activities did not show a substantial change under DQCT exposure (80 lM) (Zhang et al, 2015). Furthermore, the exposure of HepG2 cells to QCT (2.5-12.5 lg/mL) significantly increased caspase-8 and caspase-3/7 activity and cleaved PARP-1 protein .…”

“…It was revealed that GADD45GIP1 gene encodes a nuclear-localized protein that may be induced by p53 and regulates the cell cycle by inhibiting G1 to S phase progression (Nakayama et al, 2007). Considering the significant increase of the gene expression of GADD45GIP1 after the exposure of HepG2 cells to QCT (5, 15 and 30 lM) for 6 h, it was suggested that the GADD45GIP1 might be involved in S phase arrest induced by QCT (Zhang et al, 2015). As a direct transcriptional target of p53, the overexpression of p21 leads to G 1 and G 2 (Niculescu et al, 1998) or S-phase (Yadav et al, 2012) arrest.…”