Poly(ADP-ribose) polymerase-1 activity facilitates the dissociation of nuclear proteins from platinum-modified DNA.
The affinity of the poly(ADP-ribose) polymerase-1 (PARP-1) for platinum-damaged DNA was first discovered during photo-cross-linking experiments using the photoactive compound Pt-BP6 [J. Am. Chem. Soc.2004, 126, 6536-6537], an analogue of the anticancer drug cis-diamminedichloroplatinum(II), cisplatin. Although PARP inhibitors sensitize cancer cells to cisplatin, there are conflicting reports in the literature about their efficacy. In order to improve our understanding of the mechanism by which PARP inhibition might potentiate the cell-killing ability of cisplatin, and to shed light on the source of the discrepancy among different laboratories, we have in the present study probed the influence of three PARP inhibitors in four types of cancer cells, cervical (HeLa), testicular (NTera2), pancreatic (BxPC3), and osteosarcoma (U2OS), on the results of Pt-BP6 photo-cross-linking experiments and cytotoxicity assays. We find that the activity of PARP proteins following exposure to platinum-modified DNA results in the dissociation of DNA-bound proteins. PARP inhibitors were able to sensitize some, but not all, of the cell lines to cisplatin. This cell line-dependence and the potential consequences of PARP-initiated protein removal from platinum-DNA lesions are discussed. Control experiments revealed that NTera2 cells are especially sensitive to PARP inhibition.
Guggenheim
Evan R
ER
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ondrus
Alison E
AE
Movassaghi
Mohammad
M
Lippard
Stephen J
SJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D002457:Cell Extracts / Q000737:chemistry / Q000235:genetics; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry*; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C481203:CEP-6800; D002457:Cell Extracts; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin