P25 Trichodimerol induces apoptosis in A375-S2 human melanoma cells through modulation of ERK and p38 activities mediated by reactive oxygen species

Abstract

Marine microorganisms are prolific resources of novel antitumor compounds. Inducing cancer cell apoptosis has become a new possibility for tumor treatment. Reactive oxygen species (ROS) are important mediators in apoptosis induced by various antitumor agents. Trichodimerol, a secondary metabolite compound isolated from the marine fungus Trichothecium sp., has been proven to exhibit strong cytotoxic activity on several cancer cell lines. In this study, the anti-proliferative and pro-apoptotic effects of trichodimerol on A375-S2 human melanoma cells were investigated, and related mechanisms also examined. It was found that trichodimerol significantly decreased cell viability in a dose- and time-dependent manner in the MTT assay. Furthermore, trichodimerol increased the percentage of apoptotic cells in DAPI staining assays, the levels of activated caspase-3/7, and sub-G1 fraction in the cell cycle as assessed by flow cytometry, which indicates that trichodimerol has a potent pro-apoptotic effect in A375-S2 cells. Trichodimerol induced ROS levels also showed dose-dependent increases as measured by DCFH-DA, while trichodimerol induced apoptosis was effectively blocked by the ROS inhibitor N-Acetyl-L-cysteine (NAC). Western blot results showed that trichodimerol could increase phosphorylated p38 level and decrease extracellular signal-regulated kinase (ERK) and phosphorylated ERK level. In conclusion, our findings reveal that the anti-proliferative and pro-apoptotic effects of trichodimerol were mediated by ROS, while activation of p38 and inhibition of ERK may also be involved in these effects. The results suggest that trichodimerol may function as a potential therapeutic agent for the treatment of melanoma.