Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin

Jann N. Sarkaria, Randal S. Tibbetts, Ericka C. Busby, Amy P. Kennedy, David E. Hill, Robert T. Abraham

Research output: Contribution to journalArticlepeer-review

497 Scopus citations

Abstract

Members of the phosphatidylinositol-3 kinase related kinase (PIKK) family function in both cell cycle progression and DNA damage-induced cell cycle checkpoints. The fungal metabolite, wortmannin, is an effective radiosensitizer that irreversibly inhibits certain members of the PIKK family. Based on their roles in DNA damage responses, several PIKKs, DNA- dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and the ataxia- and Rad3-related protein (ATR), are potential targets for the radiosensitizing effect of wortmannin. In this report, we demonstrate that wortmannin is a relatively potent inhibitor of DNA-PK (IC50, 16 nM) and ATM (IC50, 150 nM) activities, whereas ATR activity is significantly less sensitive to this drug (IC50 1.8 μM). In intact A549 lung adenocarcinoma cells, wortmannin inhibited both DNA-PK and ATM at concentrations that correlated closely with those required for radiosensitization. Furthermore, pretreatment of A549 cells with wortmannin resulted in radioresistant DNA synthesis, a characteristic abnormality of ATM-deficient cells. These results identify wortmannin as an inhibitor of ATM activity and suggest that ATM and DNA-PK are relevant targets for the radiosensitizing effect of this drug in cancer cells.

Original languageEnglish (US)
Pages (from-to)4375-4382
Number of pages8
JournalCancer research
Volume58
Issue number19
StatePublished - Oct 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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