Open AccessThe ROS ‐induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF ‐1alpha in the NCI 60 cancer cell lines
Author(s) -
Sinnberg Tobias,
Noor Seema,
Venturelli Sascha,
Berger Alexander,
Schuler Paul,
Garbe Claus,
Busch Christian
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12207
Subject(s) - cytotoxicity , chemistry , cancer cell , ascorbic acid , reactive oxygen species , hypoxia (environmental) , pharmacology , sodium ascorbate , biochemistry , ic50 , in vitro , cancer , biology , medicine , oxygen , food science , organic chemistry
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 IC 50 values were determined on the NCI 60 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% O 2 ) globally increased the IC 50 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 IC 50 reduced the expression of GLUT ‐1 in the cancer cells. Our data show a ROS ‐induced, HIF ‐1α‐ and O 2 ‐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.