title: Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.
abstract: AW464 (NSC 706704) is a novel benzothiazole substituted quinol compound active against colon, renal and certain breast cancer cell lines. NCI COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase, which is upregulated under hypoxia. Through activity on HIF1alpha, VEGF levels are regulated and angiogenesis controlled. A thioredoxin inhibitor could therefore exhibit enhanced hypoxic toxicity and indirect antiangiogenic effects. In vitro experiments were performed on colorectal and breast cancer cell lines under both normoxic and hypoxic conditions and results compared against those obtained with normal cell lines, fibroblasts and keratinocytes. Antiangiogenic effects were studied using both large and microvessel cells. Indirect antiangiogenic effects (production of angiogenic growth factors) were studied via ELISA. We show that AW464 exerts antiproliferative effects on tumour cell lines as well as endothelial cells with an IC(50) of approximately 0.5 microM. Fibroblasts are however resistant. Proliferating, rather than quiescent, endothelial cells are sensitive to the drug indicating potential antiangiogenic rather than antivascular action. Endothelial differentiation is also inhibited in vitro. Hypoxia (1% O(2) for 48 h) sensitises colorectal cells to lower drug concentrations, and in HT29s greater inhibition of VEGF is observed under such conditions. In contrast, bFGF levels are unaffected, suggesting possible involvement of HIF1alpha. Thus, AW464 is a promising chemotherapeutic drug that may have enhanced potency under hypoxic conditions and also additional antiangiogenic activity.
authors.affiliation: Department of Clinical Oncology, City Hospital, University of Nottingham, Nottingham NG5 1PB, UK.
authors.forename: A
authors.initials: A
authors.lastname: Mukherjee
authors.forename: A D
authors.initials: AD
authors.lastname: Westwell
authors.forename: T D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: M F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: S G
authors.initials: SG
authors.lastname: Martin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003512:Cyclohexanones / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D066298:In Vitro Techniques; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003512:Cyclohexanones; D013844:Thiazoles; D016222:Fibroblast Growth Factor 2; C471867:4-(benzothiazol-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one