title: Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP‑ribose) glycohydrolase             individually, but not in combination, leads to improved chemotherapeutic efficacy             in HeLa cells.
abstract: The genome-protecting role of poly(ADP-ribose) (PAR) has identified PAR             polymerase-1 (PARP-1) and PAR glycohydrolase (PARG), two enzymes responsible for             the synthesis and hydrolysis of PAR, as chemotherapeutic targets. Each has been             previously individually evaluated in chemotherapy, but the effects of combination             PARP-1 and PARG inhibition in cancer cells are not known. Here we determined the             effects of the inhibition of PARP-1 and the absence or RNAi knockdown of PARG             on PAR synthesis, cell death after chemotherapy and long-term viability. Using             three experimental/clinical PARP-1 inhibitors in PARG-null cells, we show decreased             levels of PAR and increased short‑term and long‑term viability with each inhibitor,             with the exception of DPQ. Treatment with the experimental chemotherapeutic agent,             N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), led to increased cell death in PARG-null             cells, but decreased cell death when pretreated with each PARP-1 inhibitor. Similar             results were observed in MNNG-treated HeLa cells, where RNAi knockdown of PARG             or pretreatment with ABT-888 led to increased HeLa cell death, whereas combination             PARG RNAi knockdown + ABT-888 failed to produce increased cell death. The results             demonstrate the ability of the PARP-1 inhibitors to decrease PAR levels, maintain             viability and decrease PAR-mediated cell death after chemotherapeutic treatment             in the absence of PARG. Further, the results demonstrate that the combination             of PARP-1 and PARG inhibition in chemotherapy does not produce increased HeLa             cell death. Thus, the results indicate that inhibiting both PARP-1 and PARG, which             both are chemotherapeutic targets that increase cancer cell death, does not lead             to synergistic cell death in HeLa cells. Therefore, strategies that target PAR             metabolism for the improved treatment of cancer may be required to target PARP-1             and PARG individually in order to optimize cancer cell death.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington                     State University, Pullman, WA 99164-6534, USA.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Feng
authors.forename: David W
authors.initials: DW
authors.lastname: Koh
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase