In vitro and in vivo anti-tumor activity of CoQ0 against melanoma cells: inhibition of metastasis and induction of cell-cycle arrest and apoptosis through modulation of Wnt/β-catenin signaling pathways

Coenzyme Q(0) (CoQ(0), 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ(0) (0-20 mu M) through inhibition of Wnt/beta-catenin signaling pathway. CoQ(0) exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of beta-catenin was seen with CoQ(0) administration accompanied by a decrease in the expression of Wnt/beta-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3 beta-independent pathway. We found that CoQ(0) treatment caused G(1) cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ(0) treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ(0) markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ(0) treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ(0) significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of beta-catenin, and inhibition of cell cycle-,apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ(0) unveils a novel mechanism by down-regulating Wnt/beta-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy.