Reduced apurinic/apyrimidinic endonuclease activity enhances the antitumor activity of oxymatrine in lung cancer cells

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide and is associated with a very poor outcome. Oxymatrine exerts antitumor effects by inducing apoptosis and inhibiting the proliferation of different cancer cells; however, the anticancer effects and mechanism of action of oxymatrine have not been evaluated sufficiently in human lung cancer cells. Thus, the present study aimed to investigate the anticancer effects of oxymatrine in human lung cancer cells and identify the molecular mechanisms underlying these effects. MTT assays demonstrated that oxymatrine significantly inhibited the proliferation of A549 and H1299 cells in a time- and dose-dependent manner. In addition, flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays suggested that oxymatrine treatment may induce lung cancer cell apoptosis in a dose-dependent manner. Furthermore, we detected that oxymatrine induced a significant increase in DNA damage and the expression of PARP and phosphorylated H2AX, and a significant decrease in that of nuclear APE1 and AP endonuclease activity in A549 cells. APE1 knockdown cells (APE1shRNA) plus oxymatrine treatment reduced cells proliferation and induced apoptosis more seriously than control shRNA cells. This appeared to be a consequence of an increase in the number of apurinic/apyrimidinic (AP) sites, DNA damage, PARP and H2AX phosphorylation, which together resulted in the induction of apoptosis. In contrast, the sensitizing effects of APE1 overexpression plus oxymatrine treatment did not occur in APEOE cells. These findings reveal a potential mechanism of action for oxymatrine-induced apoptosis and suggest that oxymatrine is a promising potential therapeutic agent for the treatment of lung cancer.

Cell cycle, energy metabolism and DNA repair pathways in cancer cells are suppressed by Compound Kushen Injection

“…Our results show for the first time that not only does CKI induce DSBs, but that is also likely inhibits DNA repair by decreasing the expression of the Ku70/Ku80 complex required for NHEJ mediated DNA repair. It is worth noting however, that the reported effect of oxymatrine on DSBs [22] uses significantly higher (4–8 fold) concentrations of oxymatrine compared to our experiments. In our hands oxymatrine alone at 0.5 mg/ml showed no effect on DSBs as judged by the level of γ -H2AX after 24 or 48 h.…”

“…There is only one report in the literature of oxymatrine inducing DSBs [22] and no reports with respect to CKI. Our results show for the first time that not only does CKI induce DSBs, but that is also likely inhibits DNA repair by decreasing the expression of the Ku70/Ku80 complex required for NHEJ mediated DNA repair.…”

Protective Effects of Oxymatrine on Vascular Endothelial Cells from High-Glucose-Induced Cytotoxicity by Inhibiting the Expression of A2B Receptor

“…OMT is an alkaloid extracted from Sophora flavescens Ait, which has shown antiinflammatory, antitumor, antiviral, and anti-arrhythmic effects [30,31]. Thus its anti- [12].…”

Antioxidant Effects of Sophora davidi (Franch.) Skeels on d–Galactose–Induced Aging Model in Mice via Activating the SIRT1/p53 Pathway

“…Therefore, S. davidi is one of the main honey source plants in China. The flower, leaves, stem, fruit and root of S. davidi contain polyphenols, flavonoids, alkaloids, and other active substances that these components have anti–inflammatory, antitumor, hypoglycemic, and antioxidant effects ( Ping et al, 1999 ; Wang et al, 2016 ; Xie et al, 2017 ; Lin et al, 2019 ). Previous reports indicated that polyphenols, flavonoids, alkaloids from S. davidi have anti-aging effects ( Rosa et al, 2009 ; Ma et al, 2018 ; Hano and Tungmunnithum, 2020 ).…”