Abstract:
Mansonones are naphthoquinone-containing compounds extracted from the heartwood of Mansonia gagei. Several studies have reported that mansonones have various pharmacological activities such as antibacterial, antifungal, antioxidant, antiestrogenic, antiadipogenic and anticancer effects. A previous study reported that ether analogues of mansonone G (MG), a major compound isolated from Mansonia gagei Drumm, displayed higher antibacterial and antiadipogenic activities than parent MG. However, the anticancer activities of MG and ethoxy MG (EMG) on lung cancer cells have never been investigated. This study aimed to determine cytotoxic activities of MG and EMG and the underlying mechanism(s) in two non-small cell lung cancer cell lines, EGFR wild-type A549 cells and EGFR mutant H1975 cells. The present study demonstrated that MG and EMG significantly inhibited the viability of A549 and H1975 cells in a concentration dependent manner. It should be noted that EMG displayed higher cytotoxicity than MG in both A549 and H1975 cells. Notably, EMG was more toxic to NSCLC cells than PCS201-010 normal cells. Mechanistic studies demonstrated that EMG induced cell cycle arrest at G1 phase in A549 cells but did not induce cell cycle arrest at any phase of cell cycle in H1975 cells. Additionally, EMG induced apoptosis through ROS generation in both A549 and H1975 cells and this effect was abolished by N-acetyl cysteine (NAC). Western blotting revealed that EMG downregulated the expression of Bcl-XL and Bcl-2 and upregulated the expression of BAK and BAX in both A549 and H1975 cells. EMG activated the phosphorylation of ERK1/2 and AKT in A549 cells whereas it inhibited the phosphorylation of ERK1/2 and AKT in H1975 cells. Taken together, the results of this study suggest that the cytotoxicity of EMG is mediated via induction of cell cycle arrest and apoptosis, generation of ROS and modulation of PI3K/AKT and MAPK/ERK signaling pathways in NSCLC cells. These results suggest that EMG is a promising anticancer agent for lung cancer.
