title: 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.
abstract: Coenzyme Q0 (CoQ0, 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 CoQ0 (0-20 μM) through inhibition of Wnt/β-catenin signaling pathway. CoQ0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of β-catenin was seen with CoQ0 administration accompanied by a decrease in the expression of Wnt/β-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3β-independent pathway. We found that CoQ0 treatment caused G1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ0 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 CoQ0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of β-catenin, and inhibition of cell cycle-, apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ0 unveils a novel mechanism by down-regulating Wnt/β-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy.
authors.affiliation: Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 402, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
authors.forename: You-Cheng
authors.initials: YC
authors.lastname: Hseu
authors.affiliation: Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 402, Taiwan.
authors.forename: Varadharajan
authors.initials: V
authors.lastname: Thiyagarajan
authors.affiliation: Institute of Nutrition, China Medical University, Taichung 402, Taiwan.
authors.forename: Hsiao-Tung
authors.initials: HT
authors.lastname: Tsou
authors.affiliation: Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan.
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, Ming Chuan University, Taoyuan 333, Taiwan.
authors.forename: Hui-Jye
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung 402, Taiwan.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Graduate Institute of Veterinary Pathology, National Chung-Hsing University, Taichung 402, Taiwan.
authors.forename: Jiuun-Wang
authors.initials: JW
authors.lastname: Liao
authors.affiliation: Institute of Nutrition, China Medical University, Taichung 402, Taiwan.
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; C109863:ubiquinone-O
keywords: CoQ0; Wnt/β-catenin; apoptosis; melanoma; metastasis