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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Schulz R,Emmrich T,Lemmerhirt H,Leffler U,Sydow K,Hirt C,Kiefer T,Link A,Bednarski PJ

doi

10.1016/j.bmcl.2012.08.091

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

6712-5

issue

21

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)01102-X

journal_volume

22

pub_type

杂志文章

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