title: The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines.
abstract: Intravenous application of high-dose ascorbate is used in complementary palliative medicine to treat cancer patients. Pharmacological doses of ascorbate in the mM range induce cytotoxicity in cancer cells mediated by reactive oxygen species (ROS), namely hydrogen peroxide and ascorbyl radicals. However, little is known about intrinsic or extrinsic factors modulating this ascorbate-mediated cytotoxicity. Under normoxia and hypoxia, ascorbate IC50 values were determined on the NCI60 cancer cells. The cell cycle, the influence of cobalt chloride-induced hypoxia-inducible factor-1α (HIF-1α) and the glucose transporter 1 (GLUT-1) expression (a pro-survival HIF-1α-downstream-target) were analysed after ascorbate exposure under normoxic and hypoxic conditions. The amount of ascorbyl radicals increased with rising serum concentrations. Hypoxia (0.1% O2 ) globally increased the IC50 of ascorbate in the 60 cancer cell lines from 4.5 ± 3.6 mM to 10.1 ± 5.9 mM (2.2-fold increase, P < 0.001, Mann-Whitney t-test), thus inducing cellular resistance towards ascorbate. This ascorbate resistance depended on HIF-1α-signalling, but did not correlate with cell line-specific expression of the ascorbate transporter GLUT-1. However, under normoxic and hypoxic conditions, ascorbate treatment at the individual IC50 reduced the expression of GLUT-1 in the cancer cells. Our data show a ROS-induced, HIF-1α- and O2 -dependent cytotoxicity of ascorbate on 60 different cancer cells. This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate.
authors: Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen, Tuebingen, Germany.
authors: Tobias
authors: T
authors: Sinnberg
authors: Seema
authors: S
authors: Noor
authors: Sascha
authors: S
authors: Venturelli
authors: Alexander
authors: A
authors: Berger
authors: Paul
authors: P
authors: Schuler
authors: Claus
authors: C
authors: Garbe
authors: Christian
authors: C
authors: Busch
mesh_terms: D001205:Ascorbic Acid / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D010313:Partial Pressure; D010545:Peroxides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000633:toxicity*
chemical_list: D003470:Culture Media; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010545:Peroxides; D017382:Reactive Oxygen Species; D003035:Cobalt; C018021:cobaltous chloride; D001205:Ascorbic Acid; D010100:Oxygen
keywords: GLUT-1; HIF-1α; ROS; ascorbate; cancer; hypoxia; therapy