Journal article
MECHANISMS OF ASCORBATE-INDUCED CYTOTOXICITY IN PANCREATIC CANCER
Clinical cancer research, Vol.16(2), pp.509-520
01/15/2010
DOI: 10.1158/1078-0432.CCR-09-1713
PMCID: PMC2807999
PMID: 20068072
Abstract
Purpose: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%.
Experimental Design: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. 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 mol/L) i.p. for 2 weeks.
Results: 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.
Conclusions: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer.
Details
- Title: Subtitle
- MECHANISMS OF ASCORBATE-INDUCED CYTOTOXICITY IN PANCREATIC CANCER
- Creators
- Juan Du - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IASean M Martin - Department of Pathology, University of Iowa College of Medicine, Iowa City, IAMark Levine - Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MDBrett A Wagner - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IAGarry R Buettner - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IASih-han Wang - Department of Pathology, University of Iowa College of Medicine, Iowa City, IAAgshin F Taghiyev - Department of Pathology, University of Iowa College of Medicine, Iowa City, IAChangbin Du - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IAC. Michael Knudson - Department of Pathology, University of Iowa College of Medicine, Iowa City, IAJoseph J Cullen - Department of Surgery, University of Iowa College of Medicine, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.16(2), pp.509-520
- DOI
- 10.1158/1078-0432.CCR-09-1713
- PMID
- 20068072
- PMCID
- PMC2807999
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 01/15/2010
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984047793702771
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