title: Identification of a glutathione peroxidase inhibitor that reverses resistance to anticancer drugs in human B-cell lymphoma cell lines.
abstract: Cancer cells isolated from two patients with malignant non-Hodgkin B-cell lymphomas that became resistant to chemotherapy during clinical treatment were made ≥fourfold resistant in culture to anticancer drugs, that is cisplatin, etoposide, methotrexate and bortezomib. Because most resistant lines showed significantly increased expression of the anti-oxidative enzyme glutathione peroxidase 1 (GPx1), GPx1 was investigated as a target for inhibitor development. Virtual screening of a library of diverse structures by docking them to the active site of the X-ray crystal structure of bovine GPx1 uncovered compounds that might block the enzyme. An enzyme assay confirmed an acylhydrazone heterocycle (3) with GPx inhibitory activity. Combinations of 3 with the anticancer drugs listed above led to reversal of resistance in the lymphoma cell lines.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, 17487 Greifswald, Germany.
authors.forename: Riad
authors.initials: R
authors.lastname: Schulz
authors.forename: Thomas
authors.initials: T
authors.lastname: Emmrich
authors.forename: Heidi
authors.initials: H
authors.lastname: Lemmerhirt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Leffler
authors.forename: Kristin
authors.initials: K
authors.lastname: Sydow
authors.forename: Carsten
authors.initials: C
authors.lastname: Hirt
authors.forename: Thomas
authors.initials: T
authors.lastname: Kiefer
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D020134:Catalytic Domain; D002417:Cattle; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D016393:Lymphoma, B-Cell; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D005979:Glutathione Peroxidase