Poly(ADP-ribose) polymerase-1 activity facilitates the dissociation of nuclear proteins from platinum-modified DNA

Abstract

The affinity of the poly(ADP-ribose) polymerase-1 (PARP-1) for platinum-damaged DNA was first discovered during photo-crosscroxss-linking experiments using the photoactive compound Pt-BP6 (Zhang, C. X.; Chang, P. V.; Lippard, S. J., J. Am. Chem. Soc. 2004, 126, 6536-6537), an analogue of the anticancer drug cis-diammine-dichloroplatinum(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.

Synergistic Effect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells

“…Synergy between PARP inhibitors and platinum drugs was expected (14,15) in triple-negative breast cancer and BRCA2 ovarian cancer cells (8,17). We expected that the combination of cisplatin with olaparib showed a synergistic effect in PTEN-deficient lung cancer cell lines.…”

“…Moreover, PARP-1 was reported to bind to DNA damages induced by platinum compounds, suggesting a direct role of PARP-1 in the repair of such damages (14,15). The exquisite sensitivity of these cells to the PARP inhibitor olaparib (AZD2281), alone or in combination with cisplatin, provides strong support for olaparib as a novel targeted therapeutic against BRCA-deficient cancers (16).…”

Emerging Therapeutic Targets for Male Germ Cell Tumors

“…In vitro studies suggested that PARP inhibitors enhance cisplatin sensitivity in cisplatin-resistant GCTs cells, and that pharmacological inhibition of PARP might have clinical efficacy in GCTs [16,17]. After promising results in randomized phase II trials in patients with triple-negative breast cancer, negative results from a phase III study tempered the enthusiasm for this agent [18].…”

Synthesis and Properties of Diazirinyl Organo-Platinum Compounds for Manipulations of Photoaffinity Labeled Components

“…cisplatin) and purine base has been used in molecular biology 5) and may utilize as tag for photoaffinity labeling. Although benzophenone containing photoreactive organo-platinum complex has been reported to reveal DNA-protein interaction, [6][7][8][9] but no detailed data has been reported for efficiency of complex formation between the photoreactive organo-platinum compound and DNA before and after irradiation. In our best knowledge, organo-platinum complex, which contains diazirinyl moiety, as a photophore, and efficiency of complex formation between purine base and photoactivated diazirinyl organo-platinum compound have not been reported.…”