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A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells

Vogt, A and McDonald, PR and Tamewitz, A and Sikorski, RP and Wipf, P and Skoko, JJ and Lazo, JS (2008) A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Molecular Cancer Therapeutics, 7 (2). 330 - 340. ISSN 1535-7163

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Abstract

Mitogen-activated protein kinase phosphatase (MKP)-1 is a dual-specificity phosphatase that negatively regulates the activity of mitogen-activated kinases and that is overexpressed in human tumors. Contemporary studies suggest that induction of MKP-1 during chemotherapy may limit the efficacy of clinically used antineoplastic agents. Thus, MKP-1 is a rational target to enhance anticancer drug activity, but suitable small-molecule inhibitors of MKP-1 are currently unavailable. Here, we have used a high-content, multiparameter fluorescence-based chemical complementation assay for MKP activity in intact mammalian cells to evaluate the cellular MKP-1 and MKP-3 inhibitory activities of four previously described, quinonebased, dual-specificity phosphatase inhibitors, that is, NSC 672121, NSC 95397, DA-3003-1 (NSC 663284), and JUN-1111. All compounds induced formation of reactive oxygen species in mammalian cells, but only one (NSC 95397) inhibited cellular MKP-1 and MKP-3 with an IC50 of 13 μmol/L. Chemical induction of MKP-1 by dexamethasone protected cells from paclitaxel-induced apoptosis but had no effect on NSC 95397. NSC 95397 phenocopied the effects of MKP-1 small inhibitory RNA by reversing the cytoprotective effects of dexamethasone in paclitaxel-treated cells. Isobologram analysis revealed synergism between paclitaxel and NSC 95397 only in the presence of dexamethasone. The data show the power of a well-defined cellular assay for identifying cell-active inhibitors of MKPs and support the hypothesis that small-molecule inhibitors of MKP-1 may be useful as antineoplastic agents under conditions of high MKP-1 expression. Copyright © 2008 American Association for Cancer Research.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vogt, A
McDonald, PR
Tamewitz, A
Sikorski, RP
Wipf, Ppwipf@pitt.eduPWIPF
Skoko, JJ
Lazo, JS
Date: 1 February 2008
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 7
Number: 2
Page Range: 330 - 340
DOI or Unique Handle: 10.1158/1535-7163.mct-07-2165
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms--drug therapy; Breast Neoplasms--pathology; Cell Survival--drug effects; Cytoprotection--drug effects; Dexamethasone--antagonists & inhibitors; Dexamethasone--pharmacology; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm--drug effects; Drug Synergism; Dual Specificity Phosphatase 1--antagonists & inhibitors; Dual Specificity Phosphatase 1--metabolism; Dual Specificity Phosphatase 6--antagonists & inhibitors; Dual Specificity Phosphatase 6--metabolism; HeLa Cells; Humans; Mitogen-Activated Protein Kinase Phosphatases--antagonists & inhibitors; Models, Biological; Naphthoquinones--administration & dosage; Naphthoquinones--pharmacology; Paclitaxel--administration & dosage; Paclitaxel--pharmacology; Quinones--pharmacology; Reactive Oxygen Species--metabolism; Tumor Cells, Cultured
PubMed ID: 18245669
Date Deposited: 01 Jul 2014 17:20
Last Modified: 22 Jun 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/20677

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