Potentiation of cytotoxicity of topoisomerase i poison by concurrent and sequential treatment with the checkpoint inhibitor UCN-01 involves disparate mechanisms resulting in either p53-independent clonogenic suppression or p53-dependent mitotic catastrophe

Cancer Research
Archie N Tse, Gary K Schwartz

Abstract

UCN-01 is a potent inhibitor of the S- and G2-M-phase cell cycle checkpoints by targeting chk1 and possibly chk2 kinases. It has been shown in some, but not all, instances that UCN-01 potentiates the cytotoxicity of DNA-damaging agents selectively in p53-defective cells. We have investigated this concept in HCT116 colon cancer cells treated with the topoisomerase I poison SN-38. SN-38 alone induced a senescence-like sustained G2 arrest without apoptosis. Sequential treatment with SN-38 followed by UCN-01 resulted in enhancement of cytotoxicity by apoptosis assay, whereas the reverse sequence or concurrent treatment did not potentiate apoptosis. Real-time visualization of HCT116 cells labeled with green fluorescent protein-histone 2B or green fluorescent protein-alpha-tubulin revealed that sequential treatment resulted in G2 checkpoint abrogation, and cells entered an aberrant mitosis despite normal assembly of bipolar spindles, resulting in either apoptosis or formation of micronucleated cells. Although p53-null cells were clearly more sensitive than parental HCT116 to undergoing checkpoint abrogation and mitotic death after sequential treatment, this was not accompanied by an increased inhibition of clonogenicity over that ind...Continue Reading

References

May 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·C C Lau, A B Pardee
Dec 16, 1994·Science·L H Hartwell, M B Kastan
Jul 17, 1996·Journal of the National Cancer Institute·Q WangP M O'Connor
Oct 11, 1996·Science·Y Li, R Benezra
Sep 1, 1997·Nature Medicine·T WaldmanJ Williams
Jul 11, 1998·Molecular Cell·H HermekingB Vogelstein
Feb 22, 2000·The Journal of Biological Chemistry·P R GravesH Piwnica-Worms
Oct 29, 2000·The Journal of Biological Chemistry·X WuJ Chen
Dec 2, 2000·Nature·B B Zhou, S J Elledge
Jun 8, 2001·Molecular and Cellular Biology·H Zhao, H Piwnica-Worms
May 7, 2002·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·I B RoninsonB D Chang
Sep 18, 2002·The EMBO Journal·Maddalena DonzelliGiulio F Draetta
Oct 26, 2002·Proceedings of the National Academy of Sciences of the United States of America·Hui ZhaoHelen Piwnica-Worms
Mar 26, 2003·The Journal of Biological Chemistry·Jinwoo AhnCarol Prives
Mar 26, 2003·The Journal of Biological Chemistry·Prasad V JallepalliFred Bunz

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Citations

Apr 13, 2007·Cancer Chemotherapy and Pharmacology·Antonio JimenoRoss C Donehower
Aug 10, 2010·Cancer Chemotherapy and Pharmacology·Paula M FracassoHelen Piwnica-Worms
Feb 22, 2011·Apoptosis : an International Journal on Programmed Cell Death·Weizhen Ye, Stacy W Blain
Jul 1, 2011·Cell Death & Disease·J B StevensH H Q Heng
May 7, 2009·The Journal of Biological Chemistry·Yong-Wei ZhangYves Pommier
Apr 30, 2010·The Journal of Biological Chemistry·Da-Qiang LiRakesh Kumar
May 5, 2011·Molecular Interventions·Paul DentSteven Grant
Oct 21, 2010·Molecular Cytogenetics·Joshua B StevensHenry H Heng
Jan 29, 2013·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Puji AstutiSismindari Sudjadi
Oct 18, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Archie N TseGary K Schwartz
Aug 22, 2015·Biomolecules·Jan Benada, Libor Macurek
May 11, 2005·Expert Opinion on Investigational Drugs·Peter M Fischer, Athos Gianella-Borradori
Dec 1, 2015·Future Oncology·Elaine M Taylor, Howard D Lindsay
Nov 23, 2010·Trends in Molecular Medicine·Cynthia X MaHelen Piwnica-Worms
Mar 3, 2007·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yean-Hwei ChouChih-Hsiung Wu
Jun 7, 2013·Journal of Pharmacological Sciences·Naoto TatewakiTetsuya Konishi
Jun 10, 2008·Mechanisms of Ageing and Development·Malgorzata A SliwinskaEwa Sikora
Dec 20, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gary K Schwartz, Manish A Shah
Jul 9, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gary K Schwartz
May 10, 2005·Expert Review of Anticancer Therapy·Yan Luo, Joel D Leverson
Jan 1, 2011·Cancers·Barbara MarengoCinzia Domenicotti
Sep 15, 2007·ChemMedChem·Kenneth L Arrington, Vadim Y Dudkin
Nov 15, 2005·Annals of Oncology : Official Journal of the European Society for Medical Oncology·S J HotteH W Hirte
Nov 20, 2009·American Journal of Physiology. Renal Physiology·Ulrich BorkFrank Thévenod
Dec 22, 2004·The Journal of Biological Chemistry·Celia VogelHolger Bastians
Dec 9, 2008·The Journal of Biological Chemistry·Anastasia R DemidovaQiang Yu

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