Anticancer Drug Resistance Induced by Disruption of the Saccharomyces cerevisiae NPR2 Gene: a Novel Component Involved in Cisplatin- and Doxorubicin-Provoked Cell Kill

• DOI: 10.1124/mol.64.2.259
• Publication Date: 2003-07-17T21:32:25Z
• Authors: Paul W Schenk; Mariël Brok; Antonius W. M Boe...; Jourica A Brandsma; Hans Den Dulk; Herman Burger; Gerrit Stoter; Jaap Brouwer; Kees Nooter
• Keywords: 0303 health sciences; Saccharomyces cerevisiae Proteins; Drug Resistance; Intracellular Signaling Peptides and Proteins; Antineoplastic Agents; Saccharomyces cerevisiae; Drug Resistance, Multiple; 3. Good health; 03 medical and health sciences; Phenotype; EMC MM-03-86-08; Doxorubicin; Drug Resistance, Neoplasm; Cisplatin; Platinum

The therapeutic potential of antitumor drugs is seriously limited by the manifestation cellular drug resistance. We used budding yeast <i>Saccharomyces cerevisiae</i> as a model system to identify novel mechanisms resistance one most active anticancer agents, cisplatin. pinpointed <i>NPR2</i> (nitrogen permease regulator 2) gene whose disruption conferred In addition, we observed 4-fold cross-resistance <i>npr2</i>Δ cells (i.e., from which had been disrupted) doxorubicin, in combination with hypersensitivity cadmium chloride. Furthermore, displayed unaltered cisplatin and doxorubicin accumulation showed an enhanced rate spontaneous mutation compared isogenic parent. These data indicate that phenotype overlaps <i>sky1</i>Δ characterized previously (<i>Mol Pharmacol</i><b>61:</b>659–666, 2002). Therefore, generated double-knockout performed clonogenic survival assays for revealed <i>SKY1</i> (SR-protein-specific kinase yeast) are epistatic. strain was just resistant single-knockout either drug. conclusion, identified component involved cell kill provoked our support hypothesis may use mutual regulatory routes mediate cytotoxicity these drugs.