Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53

Stéphane Supiot, Richard P. Hill, Robert G. Bristow

Research output: Contribution to journalArticlepeer-review


Nutlin-3 is a small-molecule inhibitor that acts to inhibit MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. Whether Nutlin-3 alters cell toxicity following DNA damage under oxic versus hypoxic conditions has not been studied. The potential radio-sensitization (0-10 Gy) properties of Nutlin-3 (dose range, 2-10 μmol/L for up to 24 h) were investigated in vitro using three prostate cancer cell lines, 22RV1 [wild-type p53 (WTp53)], DU145 (mutated p53), and PC-3 (p53-null) under oxic (21% O2), hypoxic (0.2% O 2), and anoxic (0% O2) conditions. As a single agent, Nutlin-3 (2-10 μmol/L) stabilized p53 and p21WAF levels and was toxic to WTp53-22RV1 cells (IC50, 4.3 μmol/L) but had minimal toxicity toward p53-deficient cells (IC50, > 10 μmol/L). When combined with radiation under oxic conditions, Nutlin-3 decreased clonogenic survival in all three cell lines: 22RV1 [sensitizing enhancement ratio (SER), 1.24], DU145 (SER, 1.27), and PC-3 (SER, 1.12). Anoxia induced p53 protein expression in 22RV1 cells and this was augmented by Nutlin-3 treatment. Furthermore, Nutlin-3 was more effective as a radiosensitizer under hypoxic conditions particularly in WTp53-expressing cells: 22RV1 (SER, 1.78), DU145 (SER, 1.31), and PC-3 (SER, 1.28). The decrease in clonogenic survival with Nutlin-3 was not correlated to altered levels of radiation-induced apoptosis within the three cell lines. Our results indicate that Nutlin-3 can act as a radiosensitizer via p53-independent mechanisms under low O2 levels. Nutlin-3 may be a useful adjunct to improve the therapeutic ratio using precision radiotherapy targeted to hypoxic cells and warrants further study in vivo.

Original languageEnglish
Pages (from-to)993-999
Number of pages7
JournalMolecular Cancer Therapeutics
Issue number4
Publication statusPublished - 1 Apr 2008

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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