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Section of Experimental Chemotherapy, Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, the Netherlands (P.W.S., M.B., A.W.M.B., H.B., G.S., K.N.); and Medical Genetics Centre South-West Netherlands, Department of Molecular Genetics, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands (J.A.B., H.D.D., J.B.)
The therapeutic potential of antitumor drugs is seriously limited by the
manifestation of cellular drug resistance. We used the budding yeast
Saccharomyces cerevisiae as a model system to identify novel
mechanisms of resistance to one of the most active anticancer agents,
cisplatin. We pinpointed NPR2 (nitrogen permease regulator 2) as a
gene whose disruption conferred resistance to cisplatin. In addition, we
observed a 4-fold cross-resistance of yeast npr2
cells (i.e.,
cells from which the NPR2 gene had been disrupted) to the anticancer
drug doxorubicin, in combination with hypersensitivity to cadmium chloride.
Furthermore, npr2 cells displayed unaltered cellular cisplatin
and doxorubicin accumulation and showed an enhanced rate of spontaneous
mutation compared with the isogenic parent. These data indicate that the
npr2 phenotype overlaps that of the sky1 cells
that we characterized previously (Mol Pharmacol
61:659–666, 2002). Therefore, we generated yeast
npr2 sky1 double-knockout cells and performed
clonogenic survival assays for cisplatin and doxorubicin, which revealed that
NPR2 and SKY1 (SR-protein-specific kinase from budding
yeast) are epistatic. The double-knockout strain was just as resistant to
cisplatin and doxorubicin as the single-knockout strain that was most
resistant to either drug. In conclusion, we identified NPR2 as a
novel component involved in cell kill provoked by cisplatin and doxorubicin,
and our data support the hypothesis that NPR2 and SKY1 may
use mutual regulatory routes to mediate the cytotoxicity of these anticancer
drugs.
Received November 20, 2002; accepted May 9, 2003.
Address correspondence to: Dr. K. Nooter, Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Josephine Nefkens Building room Be422, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: k.nooter{at}erasmusmc.nl
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