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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2009-10-27
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pubmed:abstractText |
Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. Gain of DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that is activated by DNA damage and plays a critical role in base excision repair. Inhibition of PARP represents an attractive approach for the treatment of cancer. Previously, we have described the discovery and characterization of a potent PARP inhibitor, ABT-888. ABT-888 potentiates the activity of DNA-damaging agents such as temozolomide (TMZ) in a variety of preclinical models. We report here the generation of HCT116 cells resistant to treatment with TMZ and ABT-888 (HCT116R cells). HCT116R cells exhibit decreased H2AX phosphorylation in response to treatment with TMZ and ABT-888 relative to parental HCT116 cells. Microarray and Western blot studies indicate that HCT116R cells have decreased PARP-1 and elevated Rad51 expression levels. HCT116R cells are dependent on Rad51 for proliferation and survival, as shown by inhibition of proliferation and induction of apoptosis upon treatment with Rad51 small interfering RNA. In addition, HCT116R cells are more resistant to radiation than the parental HCT116 cells. Our study suggests that cancer cells upregulate the homologous recombination DNA repair pathway to compensate for the loss of base excision repair, which may account for the observed resistance to treatment with TMZ and ABT-888.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-((R)-2-methylpyrrolidin-2-yl)-1H-b...,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Benzimidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Dacarbazine,
http://linkedlifedata.com/resource/pubmed/chemical/H2AFX protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/PARP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Poly(ADP-ribose) Polymerases,
http://linkedlifedata.com/resource/pubmed/chemical/RAD51 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Rad51 Recombinase,
http://linkedlifedata.com/resource/pubmed/chemical/temozolomide
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1557-3125
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pubmed:author |
pubmed-author:AndersonMarkM,
pubmed-author:ChuI YIY,
pubmed-author:GirandaVincent LVL,
pubmed-author:HanEdward KEK,
pubmed-author:JohnsonEric FEF,
pubmed-author:LaskoLorenL,
pubmed-author:LeversonJoelJ,
pubmed-author:LiuXuesongX,
pubmed-author:LuoYanY,
pubmed-author:McGonigalThomasT,
pubmed-author:PalmaJoannJ,
pubmed-author:PenningThomasT,
pubmed-author:RobertsLisaL,
pubmed-author:RosenbergSaulS,
pubmed-author:SemizarovDimitriD,
pubmed-author:ShoemakerAlexander RAR,
pubmed-author:WangGangG,
pubmed-author:ZhuGui-DongGD
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pubmed:issnType |
Electronic
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pubmed:volume |
7
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1686-92
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pubmed:meshHeading |
pubmed-meshheading:19825992-Antineoplastic Agents, Alkylating,
pubmed-meshheading:19825992-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:19825992-Apoptosis,
pubmed-meshheading:19825992-Benzimidazoles,
pubmed-meshheading:19825992-Cell Line, Tumor,
pubmed-meshheading:19825992-Cell Proliferation,
pubmed-meshheading:19825992-DNA Repair,
pubmed-meshheading:19825992-Dacarbazine,
pubmed-meshheading:19825992-Down-Regulation,
pubmed-meshheading:19825992-Drug Resistance, Neoplasm,
pubmed-meshheading:19825992-Histones,
pubmed-meshheading:19825992-Humans,
pubmed-meshheading:19825992-Phosphorylation,
pubmed-meshheading:19825992-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:19825992-RNA, Small Interfering,
pubmed-meshheading:19825992-Rad51 Recombinase,
pubmed-meshheading:19825992-Recombination, Genetic,
pubmed-meshheading:19825992-Sequence Homology
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pubmed:year |
2009
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pubmed:articleTitle |
Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways.
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pubmed:affiliation |
Cancer Research, Abbott Laboratories, Abbott Park, IL 60064, USA. xuesong.liu@abbott.com
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pubmed:publicationType |
Journal Article
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