Ascorbic acid mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: a putative mechanism for anticancer properties.
Several decades back ascorbic acid was proposed as an effective anticancer agent. However, this idea remained controversial and the mechanism of action unclear. In this paper, we show that ascorbic acid at a concentration reported to be achievable through high doses of oral consumption is capable of cytotoxic action against normal cells. Several antioxidants of both animal as well as plant origin including ascorbic acid also possess prooxidant properties. Copper is an essential component of chromatin and can take part in redox reactions. Previously we have proposed a mechanism for the cytotoxic action of plant antioxidants against cancer cells that involves mobilization of endogenous copper ions and the consequent generation of reactive oxygen species. Using human peripheral lymphocytes and Comet assay we show here that ascorbic acid is able to cause oxidative DNA breakage in normal cells at a concentration of 100-200 microM. Neocuproine, a Cu(I) specific sequestering agent inhibited DNA breakage in a dose dependent manner indicating that Cu(I) is an intermediate in the DNA cleavage reaction. The results are in support of our above hypothesis that involves events that lead to a prooxidant action by antioxidants. The results would support the idea that even a plasma concentration of around 200 microM. would be sufficient to cause pharmacological tumor cell death particularly when copper levels are elevated. This would account for the observation of several decades back by Pauling and co-workers where oral doses of ascorbic acid in gram quantities were found to be effective in treating some cancers.
Bhat
Showket Hussain
SH
Department of Biochemistry, Faculty of Life Sciences, A.M.U., Aligarh 202002, UP, India.
Azmi
Asfar Sohail
AS
Hanif
Sarmad
S
Hadi
S M
SM
D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000633:toxicity*; D020552:Comet Assay; D003300:Copper / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology; D013634:Tannins / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D016877:Oxidants; D010618:Phenanthrolines; D013634:Tannins; D003300:Copper; C002701:neocuproine; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid