title: Additivity, antagonism, and synergy in arsenic trioxide-induced growth inhibition of C6 glioma cells: effects of genistein, quercetin and buthionine-sulfoximine.
abstract: Arsenic trioxide (ATO) induces clinical remission in acute promyelocytic leukemia and growth inhibition in various cancer cell lines in vitro. Recently, genistein and quercetin were reported to potentiate ATO-provoked apoptosis in leukemia and hepatocellular carcinoma cells. Genistein acted via enhanced ROS generation and quercetin via glutathione depletion. Searching for potential strategies for the treatment of malignant gliomas in this study the capacity of these flavonoids to sensitize rat C6 astroglioma cells for the cytotoxic action of ATO was investigated. ATO inhibited cell growth in a concentration- and time-dependent manner. This effect was accompanied neither by enhanced radical generation nor lipid peroxidation and was not attributed to apoptosis. ATO treatment concentration-dependently increased glutathione levels. Genistein enhanced radical generation. Combined with ATO it inhibited cell growth additively. Additivity was also obtained after cotreatment with ATO and H2O2. Quercetin acted antagonistically on ATO-induced growth inhibition. Quercetin increased glutathione levels. In contrast, buthionine-sulfoximine (BSO) depleted cellular glutathione and acted synergistically with ATO. In conclusion, in C6 cells neither genistein nor quercetin are suited as sensitizing agent, in contrast to BSO. Depletion of cellular glutathione content rather than an increase of ROS generation plays a central role in the enhancement of ATO-toxicity in C6 cells.
authors.affiliation: Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Klauser
authors.affiliation: Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gülden
authors.affiliation: Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany.
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
authors.affiliation: Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Seibert
authors.affiliation: Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany. Electronic address: Seibert@toxi.uni-kiel.de.
authors.forename: Hasso
authors.initials: H
authors.lastname: Seibert
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D019833:Genistein / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D010087:Oxides / Q000633:toxicity*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats
chemical_list: D001152:Arsenicals; D010087:Oxides; D019328:Buthionine Sulfoximine; D011794:Quercetin; D019833:Genistein; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Combination effects; Genistein; Glutathione; Quercetin; Sensitization