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Cranberry Juice Extract, A Mild Prooxidant with Cytotoxic Properties Independent of Reactive Oxygen Species

Babich H, Ickow IM, Weisburg JH, Zuckerbraun HL, Schuck AG
Phytother Res DOI: 10.1002/ptr.3735

A cranberry juice extract (CJE), rich in proanthocyanidins, had weak prooxidant properties, generating low
levels of hydrogen peroxide (H2O2) and superoxide. Generation of H2O2 was pH dependent, increasing at
alkaline pH, and was lowered in the presence of catalase and, to a lesser extent, of superoxide dismutase
(SOD). Growth inhibition and cytotoxicity were noted towards human oral carcinoma HSC-2 cells, with midpoint
cytotoxicity at 200mg/mL CJE, but not towards human gingival HF-1 fibroblasts. Being a mild prooxidant,
CJE toxicity was unaffected by exogenous catalase and pyruvate, scavengers of H2O2, but triggered intracellular
synthesis of reduced glutathione, as confirmed by cell staining with Cell Tracker™ Green. The presence of
exogenous SOD potentiated the toxicity of CJE, possibly by stabilizing the CJE phenols and hindering their
degradative autooxidation. Conversely, ‘spent’ CJE, i.e. CJE added to cell culture medium and incubated for
24 h at 37 C prior to use, was much less toxic to HSC-2 cells than was freshly prepared CJE. These differences
in toxicity between SOD-stabilized CJE, freshly prepared CJE, and ‘spent’ CJE were confirmed in HSC-2 cells
stained with aceto-orcein, which also indicated that the mode of cell death was by the induction of apoptosis.