Anticancer effects of mansonone G derivative on human colorectal cancer cells

Abstract

Mansonone G (MG), 1,2-naphthoquinone, isolated from the heartwood of Mansonia gagei Drumm (Chan-Cha-Mod), exhibited several pharmacological effects including anti-bacterial, anti-estrogenic and anti-adipogenic effects. However, anticancer activity of MG and its derivatives on colorectal cancer (CRC) has never been investigated. Therefore, the objective of this study was to investigate the cytotoxic effect of MG and its derivatives and to determine the mechanism(s) underlying cytotoxicity of the most potent MG derivative on two CRC cell lines, HCT-116 cells carrying p53 wild-type and HT-29 cells carrying p53 mutant. In the present study, MG and its derivatives could inhibit viability of HCT-116 and HT-29 cells in a concentration-dependent manner. Of all MG and its derivatives, G07 was the most potent cytotoxic agent toward the cancer cells and less toxic to normal cells, PCS201-010 and CRL-1790. Mechanistic studies revealed that G07 could induce apoptosis through ROS generation in both HCT-116 and HT-29 cells and this effect was abolished by N-acetyl cysteine (NAC). Western blot analysis revealed that G07 downregulated the expression of Bcl-2 and Bcl-xl proteins in both cells and upregulated the expression of Bak protein in HT-29 cells. Moreover, G07 downregulated AKT signaling pathway and modulated ERK1/2 signaling pathway by inhibiting ERK1/2 phosphorylation in HCT-116 cells and activating ERK1/2 phosphorylation in HT-29 cells. Taken together, the present study demonstrated that G07 exerted a potent anticancer effect toward human colorectal cancer cells which was associated with induction of apoptosis, generation of ROS and modulation of ERK1/2 and AKT signaling pathways, suggesting that G07 is a promising compound for further development as an anticancer agent in CRC treatment.