The Cockayne syndrome group B DNA repair protein as an anti-cancer target.
Cells from individuals with Cockayne syndrome (CS) have a defect in transcription-coupled DNA repair (TCR), which rapidly corrects certain DNA lesions located on the transcribed strand of active genes. Despite this DNA repair defect, individuals with CS (of which there are two complementation groups, CSA and CSB) do not demonstrate an elevated incidence of cancer. Recently, we demonstrated that disruption of the CSB gene reduces the spontaneous tumor rate in cancer predisposed Ink4a/ARF-/- mice as well as causing their embryo fibroblasts to proliferate more slowly and be more sensitive to UV-induced apoptosis. In the present study we characterized phosphorothioate backbone antisense oligodeoxynucleotides (AOs) that reduced the levels of CSB mRNA in A2780/CP70 ovarian carcinoma cells. The AOs caused the cells to proliferate more slowly and made them more sensitive to either cisplatin or oxaliplatin. The AOs also enhanced the cytotoxicity of hydrogen peroxide and gamma-radiation, both of which can induce oxidative DNA lesions, which are subject to TCR. The AOs did not potentiate the cytotoxicity of topotecan, which induces DNA strand breaks. Chemically modified (<mixed backbone>) AOs (MBOs) targeting CSB were able to potentiate the anti-tumor effect of cisplatin against A2780/CP70 tumor xenografts formed in nude mice. The MBOs enabled a non-toxic (3 mg/kg) dose of cisplatin to have the same degree of anti-tumor efficacy as a more toxic (5 mg/kg) cisplatin dose. Collectively, these results suggest that the CSB gene product may be viewed as an anti-cancer target.
Lu
Y
Y
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mani
S
S
Kandimalla
E R
ER
Yu
D
D
Agrawal
S
S
States
J C
JC
Bregman
D B
DB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003057:Cockayne Syndrome / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077150:Oxaliplatin; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013873:Thionucleotides / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D009944:Organoplatinum Compounds; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D013873:Thionucleotides; D000077150:Oxaliplatin; D004265:DNA Helicases; C078673:ERCC6 protein, human; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes; D002945:Cisplatin