title: Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.
abstract: Because 5-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on B16-F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents dacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (P < 0.0001) and NOD-scid tumor bearing mice (P < 0.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted.
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, USA.
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Serrano
authors.affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nermi L
authors.initials: NL
authors.lastname: Parrow
authors.affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Pierre-Christian
authors.initials: PC
authors.lastname: Violet
authors.affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Yang
authors.affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zornjak
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Basseville
authors.affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: markl@intra.niddk.nih.gov.
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001205:Ascorbic Acid; D003606:Dacarbazine; D006657:Histones; C475961:gamma-H2AX protein, mouse
keywords: Ascorbate; Cancer; Hydrogen peroxide; Melanoma; Prooxidant; Vitamin C