Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.
Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.
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DOI：
10.1158/1078-0432.ccr-09-1713
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Cullen JJ
中科院分区：
文献类型：
--
作者：
Du J;Martin SM;Levine M;Wagner BA;Buettner GR;Wang SH;Taghiyev AF;Du C;Knudson CM;Cullen JJ
Pharmacological concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with intravenous dosing would be cytotoxic in pancreatic cancer where the five-year survival is < 3%. Pancreatic cancer cell lines were treated with ascorbate (0, 5, and 10 mM) for one hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered subcutaneously into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 M) i.p. for two weeks. There was a time and dose-dependent increase in measured H2O2 production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines, but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H2O2. Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival. These results demonstrate that pharmacological doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer.
