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Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy

Chen, Pinga,b,c; Yu, Junb,c; Chalmers, Brainb,c; Drisko, Jeannec; Yang, Jund; Li, Benyid; Chen, Qib,c

doi: 10.1097/CAD.0b013e32834fd01f
Preclinical Reports

Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer.

aDepartment of Genetic and Molecular Biology, Xi’an Jiaotong University School of Medicine, Xi’an, China

bDepartment of Pharmacology, Toxicology and Therapeutics

cProgram in Integrative Medicine

dDepartment of Urology, University of Kansas Medical Center, Kansas City, Kansas, USA

Correspondence to Dr Qi Chen, PhD, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd. MS1017, Kansas City, KS 66160, USA Tel: +913 588 3690; fax: +913 945 6751; e-mail: qchen@kumc.edu

Received August 26, 2011

Accepted November 29, 2011

© 2012 Lippincott Williams & Wilkins, Inc.