Article

Potentiation of temozolomide cytotoxicity by inhibition of DNA polymerase beta is accentuated by BRCA2 mutation.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut 06520-8040, USA.
Cancer Research (impact factor: 7.86). 12/2009; 70(1):409-17. DOI:10.1158/0008-5472.CAN-09-1353 pp.409-17
Source: PubMed

ABSTRACT Base excision repair (BER) plays a critical role in the repair of bases damaged by oxidative metabolism or alkylating agents, such as those commonly used in cancer therapy. Incomplete BER generates intermediates that require activation of homology-dependent DNA repair to resolve. We investigated the effects of lithocholic acid (LCA), an inhibitor of the key BER enzyme DNA polymerase beta (pol beta), in cells deficient in expression of the homology-dependent repair factor BRCA2. In vitro studies show that LCA suppresses the DNA polymerase and 5'-deoxyribose phosphate lyase activities of DNA pol beta by preventing the formation of a stable pol beta-DNA complex, reducing BER effectiveness. Cytotoxicity assays based on colony formation revealed that LCA exhibits synergism with the alkylating agent temozolomide, which engages BER through DNA methylation, and that the degree of synergism is increased in cells lacking functional BRCA2. BRCA2-deficient cells also showed heightened susceptibility to both LCA and temozolomide individually. The potentiation of temozolomide cytotoxicity by LCA owes to the conversion of single-stranded DNA breaks generated through incomplete BER of methylated nucleotides into double-stranded breaks during DNA replication, as indicated by gammaH2AX immunofluorescence. Death seems to be induced in cotreated cells through an accumulation of persistent double-stranded DNA breaks. Mutations of the BRCA2 gene have been extensively characterized and are present in various cancers, implying that inhibition of BER may offer a means to augment tumor selectivity in the use of conventional cancer therapies.

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Keywords

5'-deoxyribose phosphate lyase activities
 
alkylating agent temozolomide
 
alkylating agents
 
BRCA2-deficient cells
 
cancer therapy
 
cells deficient
 
conventional cancer therapies
 
cotreated cells
 
DNA pol beta
 
DNA replication
 
double-stranded breaks
 
engages BER
 
homology-dependent DNA
 
incomplete BER
 
LCA exhibits synergism
 
LCA suppresses
 
persistent double-stranded DNA breaks
 
single-stranded DNA breaks
 
stable pol beta-DNA complex
 
various cancers
 

Gregory C Stachelek