Identification of a glutathione peroxidase inhibitor that reverses resistance to anticancer drugs in human B-cell lymphoma cell lines |
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Authors: | Riad Schulz Thomas Emmrich Heidi Lemmerhirt Ulrike Leffler Kristin Sydow Carsten Hirt Thomas Kiefer Andreas Link Patrick J Bednarski |
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Institution: | 1. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, 17487 Greifswald, Germany;2. Clinic for Haematology and Oncology, Ernst-Moritz-Arndt University Greifswald, 17475 Greifswald, Germany |
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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. |
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Keywords: | Anticancer drug Inhibitor Resistance Glutathione peroxidase Non-Hodgkins’s lymphoma |
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