Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53

Molecular Cancer Therapeutics
Stéphane SupiotRobert G Bristow

Abstract

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 radiosensitization (0-10 Gy) properties of Nutlin-3 (dose range, 2-10 micromol/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% O(2)), hypoxic (0.2% O(2)), and anoxic (0% O(2)) conditions. As a single agent, Nutlin-3 (2-10 micromol/L) stabilized p53 and p21(WAF) levels and was toxic to WTp53-22RV1 cells (IC(50), 4.3 micromol/L) but had minimal toxicity toward p53-deficient cells (IC(50), >10 micromol/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),...Continue Reading

References

May 19, 2001·European Journal of Biochemistry·E Appella, C W Anderson
Dec 24, 2002·Cancer Biology & Therapy·J Martin Brown
Mar 29, 2003·Prostate Cancer and Prostatic Diseases·G P BromfieldR G Bristow
Jan 6, 2004·Science·Lyubomir T VassilevEmily A Liu
Feb 18, 2004·International Journal of Radiation Oncology, Biology, Physics·Chris ParkerRichard P Hill
Feb 24, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhuo ZhangRuiwen Zhang
Mar 17, 2004·Molecular and Cellular Biology·Julia I BárdosMargaret Ashcroft
Jun 2, 2004·Nature Reviews. Cancer·J Martin Brown, William R Wilson
Aug 17, 2004·The Journal of Biological Chemistry·Mu-Shui Dai, Hua Lu
Feb 3, 2005·The Lancet Oncology·Søren M Bentzen
Mar 1, 2005·The Journal of Biological Chemistry·Jodi R AltChristine M Eischen
Jul 20, 2005·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Alice X MengRobert G Bristow
Oct 6, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Stephane SupiotMichel Cherel
Dec 28, 2005·Seminars in Radiation Oncology·Ananya ChoudhuryRobert G Bristow
Mar 1, 2006·Molecular Cancer Therapeutics·Carolyn CaoBo Lu
Mar 28, 2006·International Journal of Radiation Oncology, Biology, Physics·Dawn M CarnellPeter J Hoskin
Mar 16, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Einar K RofstadElse-Beate M Ruud
May 29, 2007·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Robert G BristowDanny Vesprini

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Citations

Mar 5, 2009·Apoptosis : an International Journal on Programmed Cell Death·Chao Lu, Wafik S El-Deiry
Sep 29, 2011·Clinical & Experimental Metastasis·WeiWei XiaoYong Li
Oct 16, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Fan ZhangClinton F Stewart
Nov 15, 2012·Genes & Cancer·Alexia N Melo, Christine M Eischen
Mar 1, 2014·Nature Reviews. Drug Discovery·Kian Hoe KhooDavid P Lane
Jan 22, 2014·Cancer Metastasis Reviews·Lei ChangYong Li
May 22, 2009·Expert Opinion on Therapeutic Patents·Francis DumontPierre Bischoff
Oct 28, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Erik O PettersenDan Cojocari
Jul 2, 2010·Acta Oncologica·Adrian S IshkanianRobert G Bristow
Feb 19, 2010·Translational Oncology·Zhen Wang, Yi Sun
Jun 21, 2011·Cancer radiothérapie : journal de la Société française de radiothérapie oncologique·C ChargariE Deutsch
Sep 14, 2010·Seminars in Radiation Oncology·John Thoms, Robert G Bristow
Aug 24, 2010·Cancer radiothérapie : journal de la Société française de radiothérapie oncologique·S SupiotP Fenoglietto
Jun 2, 2015·Molecular Therapy. Methods & Clinical Development·Takahiro OchiyaHideya Endo
Sep 10, 2011·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Helen ZhaoRobert G Bristow
Jan 17, 2013·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Vincent A PotironStéphane Supiot
Apr 25, 2016·Neoplasia : an International Journal for Oncology Research·Felix Y FengDaniel A Hamstra
Jun 28, 2013·Journal of Medicinal Chemistry·Alessia BertaminoIsabel Gomez-Monterrey
Oct 26, 2016·Advances in Biological Regulation·James A McCubreyLinda S Steelman
Dec 10, 2016·Journal of Molecular Cell Biology·Christine M Eischen
Apr 27, 2013·Technology in Cancer Research & Treatment·Yao-Dong WangJian-Xing Liao
Oct 27, 2010·Nature Reviews. Clinical Oncology·Chit Fang CheokDavid P Lane
Nov 27, 2016·Oncotarget·Karin HientzThomas Efferth
Aug 12, 2017·Experimental & Molecular Medicine·Dong Min LeeKyeong Sook Choi
Aug 28, 2019·Journal of Cellular Biochemistry·Babak BajelanFarzad Rajaei
Jul 30, 2020·Scientific Reports·Beata HatTomasz Lipniacki
Jul 15, 2015·Molecular Cancer Therapeutics·Lauryn R WernerPaul M Harari
Jun 24, 2009·Chemical Reviews·Mats Ljungman
Jul 27, 2021·Frontiers in Oncology·Xanthene MilesJulie Bolcaen
Dec 17, 2021·Cellular & Molecular Biology Letters·Lucia HaronikovaBorivoj Vojtesek

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