Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression

Dilip Jain, Nila Patel, Melanie Shelton, Alakananda Basu, Rouel Roque, Wolfram Siede

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Purpose: NSC109268 has been described previously as inhibitor of proteasomal degradation and of phosphatase 2Cα. In a yeast screen, we isolated NSC109268 as an agent altering sensitivity to DNA-damaging agents. We found that NSC109268 and the related compound NSC109272 enhance cellular sensitivity to cis- and transplatin but reduce sensitivity to nitrogen mustard. We explored if similar effects could be found in human cancer cells and if cell cycle analysis could hint at the underlying molecular mechanism. Methods: Haploid yeast cells were treated in suspension with platinum agents and nitrogen mustard alone or in combination with NSC compounds, and survival was measured by colony-formation assays. Sensitivity of ovarian and prostate cancer cells toward these treatments was evaluated using the MTS assay. Cell cycle progression was determined by flow cytometry. Results: The enhancement of cisplatin sensitivity by NSC109268 found in yeast was confirmed in cisplatin-sensitive and cisplatin-resistant human ovarian cancer lines and in prostate cancer cells. In yeast and in human carcinoma cells, a correlation of enhanced sensitivity with delaying S-phase progression was revealed. Conclusion: The known activities of NSC109268 as proteasome or phosphatase inhibitor could explain the phenotype of S-phase delay by assuming a higher initial DNA damage load, inhibition of DNA translesion synthesis or extended checkpoint arrest.

Original languageEnglish
Pages (from-to)945-952
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number5
DOIs
StatePublished - 1 Oct 2010

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Saccharomycetales
S Phase
Yeast
Cisplatin
Cells
Yeasts
Mechlorethamine
Neoplasms
Phosphoric Monoester Hydrolases
Ovarian Neoplasms
Prostatic Neoplasms
Cell Cycle
Assays
DNA
Haploidy
Proteasome Endopeptidase Complex
Platinum
DNA Damage
Suspensions
Flow cytometry

Keywords

  • Cisplatin
  • Ovarian cancer
  • Proteasome inhibitor
  • Resistance
  • S-phase
  • Yeast

Cite this

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title = "Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression",
abstract = "Purpose: NSC109268 has been described previously as inhibitor of proteasomal degradation and of phosphatase 2Cα. In a yeast screen, we isolated NSC109268 as an agent altering sensitivity to DNA-damaging agents. We found that NSC109268 and the related compound NSC109272 enhance cellular sensitivity to cis- and transplatin but reduce sensitivity to nitrogen mustard. We explored if similar effects could be found in human cancer cells and if cell cycle analysis could hint at the underlying molecular mechanism. Methods: Haploid yeast cells were treated in suspension with platinum agents and nitrogen mustard alone or in combination with NSC compounds, and survival was measured by colony-formation assays. Sensitivity of ovarian and prostate cancer cells toward these treatments was evaluated using the MTS assay. Cell cycle progression was determined by flow cytometry. Results: The enhancement of cisplatin sensitivity by NSC109268 found in yeast was confirmed in cisplatin-sensitive and cisplatin-resistant human ovarian cancer lines and in prostate cancer cells. In yeast and in human carcinoma cells, a correlation of enhanced sensitivity with delaying S-phase progression was revealed. Conclusion: The known activities of NSC109268 as proteasome or phosphatase inhibitor could explain the phenotype of S-phase delay by assuming a higher initial DNA damage load, inhibition of DNA translesion synthesis or extended checkpoint arrest.",
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Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression. / Jain, Dilip; Patel, Nila; Shelton, Melanie; Basu, Alakananda; Roque, Rouel; Siede, Wolfram.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 5, 01.10.2010, p. 945-952.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression

AU - Jain, Dilip

AU - Patel, Nila

AU - Shelton, Melanie

AU - Basu, Alakananda

AU - Roque, Rouel

AU - Siede, Wolfram

PY - 2010/10/1

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AB - Purpose: NSC109268 has been described previously as inhibitor of proteasomal degradation and of phosphatase 2Cα. In a yeast screen, we isolated NSC109268 as an agent altering sensitivity to DNA-damaging agents. We found that NSC109268 and the related compound NSC109272 enhance cellular sensitivity to cis- and transplatin but reduce sensitivity to nitrogen mustard. We explored if similar effects could be found in human cancer cells and if cell cycle analysis could hint at the underlying molecular mechanism. Methods: Haploid yeast cells were treated in suspension with platinum agents and nitrogen mustard alone or in combination with NSC compounds, and survival was measured by colony-formation assays. Sensitivity of ovarian and prostate cancer cells toward these treatments was evaluated using the MTS assay. Cell cycle progression was determined by flow cytometry. Results: The enhancement of cisplatin sensitivity by NSC109268 found in yeast was confirmed in cisplatin-sensitive and cisplatin-resistant human ovarian cancer lines and in prostate cancer cells. In yeast and in human carcinoma cells, a correlation of enhanced sensitivity with delaying S-phase progression was revealed. Conclusion: The known activities of NSC109268 as proteasome or phosphatase inhibitor could explain the phenotype of S-phase delay by assuming a higher initial DNA damage load, inhibition of DNA translesion synthesis or extended checkpoint arrest.

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