title: Vitamin C at high concentrations induces cytotoxicity in malignant melanoma but promotes tumor growth at low concentrations.
abstract: Vitamin C has been used in complementary and alternative medicine for cancers regardless of its ineffectiveness in clinical trials and the paradoxical effects antioxidants have on cancer. Vitamin C was found to induce cytotoxicity against cancers. However, the mechanisms of action have not been fully elucidated, and the effects of vitamin C on human malignant melanoma have not been examined. This study revealed that vitamin C at millimolar concentrations significantly reduced the cell viability as well as invasiveness, and induced apoptosis in human malignant melanoma cells. Vitamin C displayed stronger cytotoxicity against the Vemurafenib-resistance cell line A2058 compared with SK-MEL-28. In contrast, vitamin C at micromolar concentrations promoted cell growth, migration and cell cycle progression, and protected against mitochondrial stress. Vemurafenib paradoxically activated the RAS-RAF-MEK-ERK signaling pathway in the Vemurafenib-resistant A2058, however, vitamin C abolished the activations. Vitamin C displayed synergistic cytotoxicity with Vemurafenib against the Vemurafenib-resistant A2058. In vivo assay suggested that lower dosage (equivalent to 0.5 g/70 kg) of vitamin C administered orally increased the melanoma growth. Therefore, vitamin C may exert pro- or anti-melanoma effect depending on concentration. The combination of vitamin C at high dosage and Vemurafenib is promising in overcoming the action of drug resistance.
authors.affiliation: Department of Biological Sciences, Emporia State University, Emporia, Kansas.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Emporia State University, Emporia, Kansas.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yan
authors.forename: Younan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Biological Sciences, Emporia State University, Emporia, Kansas.
authors.forename: Yixin
authors.identifier: 0000-0001-7997-3849
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077484:Vemurafenib; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D001205:Ascorbic Acid
keywords: RAS-RAF-MEK-ERK signaling pathway; apoptosis; invasiveness; malignant melanoma; vitamin C