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Inhibition of poly(ADP‐ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks
Author(s) -
Golla Radha M.,
Li Min,
Shen Yulei,
Ji Ming,
Yan Ying,
Fu Kai,
Greiner Timothy C.,
McKeithan Timothy W.,
Chan Wing C.
Publication year - 2012
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.1020
Subject(s) - cancer research , mantle cell lymphoma , dna repair , dna damage , ataxia telangiectasia , poly adp ribose polymerase , chemistry , microbiology and biotechnology , synthetic lethality , biology , polymerase , dna , lymphoma , biochemistry , immunology
Abstract There is a high incidence of genomic aberration of ataxia telangiectasia mutated ( ATM ) and genes encoding proteins involved in the ATM pathway in mantle cell lymphoma (MCL). It has been shown that poly(ADP‐ribose) polymerase inhibitor (PARPi) strongly enhances the cytotoxicity of agents, causing single‐strand DNA breaks in cells with impaired homologous recombination repair. Here, we show that PARPi AG14361 potentiates the cytotoxicity induced by topotecan treatment in MCL cell lines, which was not dependent on either TP53 or CHEK2 status. Inhibition and/or knockdown of ATM and BRCA2 did not potentiate the cytotoxic effect of treatment with PARPi and topotecan. With loss of function of ATM, other kinases can still mediate activation of ATM substrates as demonstrated by continued phosphorylation of CHEK2 (Thr‐68), although attenuated and delayed. These results suggest that PARPi may enhance the therapeutic efficacy of DNA damaging agents on MCL through TP53‐independent mechanisms without requiring the inhibition of either ATM or BRCA2. Copyright © 2011 John Wiley & Sons, Ltd.