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Molecular Pharmacology

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Research ArticleArticle

Dysregulation of Purine Nucleotide Biosynthesis Pathways Modulates Cisplatin Cytotoxicity in Saccharomyces cerevisiae

David Kowalski, Lakshmi Pendyala, Bertrand Daignan-Fornier, Stephen B. Howell and Ruea-Yea Huang
Molecular Pharmacology October 2008, 74 (4) 1092-1100; DOI: https://doi.org/10.1124/mol.108.048256
David Kowalski
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Lakshmi Pendyala
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Bertrand Daignan-Fornier
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Stephen B. Howell
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Ruea-Yea Huang
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Abstract

We found previously that inactivation of the FCY2 gene, encoding a purine-cytosine permease, or the HPT1 gene, encoding the hypoxanthine guanine phosphoribosyl transferase, enhances cisplatin resistance in yeast cells. Here, we report that in addition to fcy2Δ and hpt1Δ mutants in the salvage pathway of purine nucleotide biosynthesis, mutants in the de novo pathway that disable the feedback inhibition of AMP and GMP biosynthesis also enhanced cisplatin resistance. An activity-enhancing mutant of the ADE4 gene, which constitutively synthesizes AMP and excretes hypoxanthine, and a GMP kinase mutant (guk1), which accumulates GMP and feedback inhibits Hpt1 function, both enhanced resistance to cisplatin. In addition, overexpression of the ADE4 gene in wild-type cells, which increases de novo synthesis of purine nucleotides, also resulted in elevated cisplatin resistance. Cisplatin cytotoxicity in wild-type cells was abolished by low concentration of extracellular purines (adenine, hypoxanthine, and guanine) but not cytosine. Inhibition of cytotoxicity by exogenous adenine was accompanied by a reduction of DNA-bound cisplatin in wild-type cells. As a membrane permease, Fcy2 may mediate limited cisplatin transport because cisplatin accumulation in whole cells was slightly affected in the fcy2Δ mutant. However, the fcy2Δ mutant had a greater effect on the amount of DNA-bound cisplatin, which decreased to 50 to 60% of that in the wild-type cells. Taken together, our results indicate that dysregulation of the purine nucleotide biosynthesis pathways and the addition of exogenous purines can modulate cisplatin cytotoxicity in Saccharomyces cerevisiae.

Footnotes

  • This work was supported by National Institutes of Health grants CA 107303-02 (to R.H.) and GM30614-19 (to D.K.).

  • ABBREVIATIONS: cDDP, cis-diamminedichloroplatinum II (cisplatin); ADE, adenine; PCR, polymerase chain reaction; IMP, inosine 5′-monophosphate; PRPP, 5-phosphoribosyl 1-pyrophosphate; WT, wild type; SDM, synthetic defined yeast nitrogen base media; GFP, green fluorescence protein.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received April 24, 2008.
    • Accepted July 7, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (4)
Molecular Pharmacology
Vol. 74, Issue 4
1 Oct 2008
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Research ArticleArticle

Dysregulation of Purine Nucleotide Biosynthesis Pathways Modulates Cisplatin Cytotoxicity in Saccharomyces cerevisiae

David Kowalski, Lakshmi Pendyala, Bertrand Daignan-Fornier, Stephen B. Howell and Ruea-Yea Huang
Molecular Pharmacology October 1, 2008, 74 (4) 1092-1100; DOI: https://doi.org/10.1124/mol.108.048256

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Research ArticleArticle

Dysregulation of Purine Nucleotide Biosynthesis Pathways Modulates Cisplatin Cytotoxicity in Saccharomyces cerevisiae

David Kowalski, Lakshmi Pendyala, Bertrand Daignan-Fornier, Stephen B. Howell and Ruea-Yea Huang
Molecular Pharmacology October 1, 2008, 74 (4) 1092-1100; DOI: https://doi.org/10.1124/mol.108.048256
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