Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept.
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ABSTRACT:
SUBMITTER: Szabo C
PROVIDER: S-EPMC7605157 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Myocardial ischaemia/reperfusion (I/R) injury attenuates the beneficial effects of reperfusion therapy. Poly(ADP-ribose) polymerase (PARP) is overactivated during myocardial I/R injury. Mitophagy plays a critical role in the development of myocardial I/R injury. However, the effect of PARP activation on mitophagy in cardiomyocytes is unknown. In this study, we found that I/R induced PARP activation and mitophagy in mouse hearts. Poly(ADP-ribose) polymerase inhibition reduced the infarct size and suppressed mitophagy after myocardial I/R injury. In vitro, hypoxia/reoxygenation (H/R) activated PARP, promoted mitophagy and induced cell apoptosis in cardiomyocytes. Poly(ADP-ribose) polymerase inhibition suppressed H/R-induced mitophagy and cell apoptosis. Parkin knockdown with lentivirus vectors inhibited mitophagy and prevented cell apoptosis in H/R-treated cells. Poly(ADP-ribose) polymerase inhibition prevented the loss of the mitochondrial membrane potential (ΔΨm). Cyclosporin A maintained ΔΨm and suppressed mitophagy but FCCP reduced the effect of PARP inhibition on ΔΨm and promoted mitophagy, indicating the critical role of ΔΨm in H/R-induced mitophagy. Furthermore, reactive oxygen species (ROS) and poly(ADP-ribosylation) of CypD and TSPO might contribute to the regulation of ΔΨm by PARP. Our findings thus suggest that PARP inhibition protects against I/R-induced cell apoptosis by suppressing excessive mitophagy via the ΔΨm/Parkin pathway.
| S-EPMC6787458 | biostudies-literature
Project description:Purpose of reviewTo highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials.Recent findingsThe use of PARP inhibition (PARPi) for frontline maintenance offers substantial clinical benefit in patients with homologous recombination-deficient tumors. However, expanding PARPi from recurrent therapy to frontline maintenance may potentially result in more PARPi resistant tumors earlier in the treatment continuum and data for the use of PARPi after PARPi remain limited. Clinical evidence demonstrates tumors may develop resistance to PARPi through demethylation of the BRCA promoter or BRCA reversion mutations. Multiple clinical trials investigating therapeutic strategies to overcome resistance, such as combinations of PARPi with antiangiogenic drugs, PI3K/AKT/mTOR, or MEK inhibitors have already been reported and more are ongoing. Furthermore, increasing the amount of DNA damage in the tumor using chemotherapy or cell cycle inhibitors such as ATM, ATR/CHK1/WEE1 is also under exploration.SummaryThere is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance. PARPi represent a class of drugs that have significantly impacted the treatment and maintenance of ovarian cancer; as the use of PARPi increases, better understanding of resistance mechanisms is essential.
| S-EPMC7958870 | biostudies-literature
Project description:BackgroundDespite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer ("BRCAness" ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10-15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles.ConclusionThis review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy.
| S-EPMC5024442 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine-specific histone demethylase-1A inhibitors or histone deacetylase inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
| S-EPMC6215877 | biostudies-literature
Project description:BackgroundHypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain.ObjectiveAim of this study was to explore the effect of TES448 (PARP-1-inhibitor) and hypothermia after an ischemic insult.Design and methods10-day-old Wistar rats underwent HI. TES448 was given 10?min, 3?hrs, and 6?hrs after hypoxia. Hypothermia was started 30?min after HI and brains were dissected at P12. Western blotting and histological staining were used to evaluate for degree of injury.ResultsProtein expression of PARP-1 levels was diminished after TES448 treatment. Cresyl violet and TUNEL staining revealed decreased injury in male rat pups following TES448 and combined treatment. Female rats showed increased numbers of TUNEL-positive cells after combined therapy. TES448 inhibited microglia activation after hypoxic-ischemic injury. A cellular response including NeuN, Olig2, and MBP was not affected by PARP-1-inhibition.ConclusionsInhibition of PARP-1 and hypothermia lead to an alteration of injury but this effect is sexually dimorphic.
| S-EPMC5494065 | biostudies-literature
Project description:Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.
| S-EPMC4718819 | biostudies-literature
Project description:The ability of 7-methylguanine, a nucleic acid metabolite, to inhibit poly(ADP-ribose)polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2) has been identified in silico and studied experimentally. The amino group at position 2 and the methyl group at position 7 were shown to be important substituents for the efficient binding of purine derivatives to PARPs. The activity of both tested enzymes, PARP-1 and PARP-2, was suppressed by 7-methylguanine with IC50 values of 150 and 50 μM, respectively. At the PARP inhibitory concentration, 7-methylguanine itself was not cytotoxic, but it was able to accelerate apoptotic death of BRCA1-deficient breast cancer cells induced by cisplatin and doxorubicin, the widely used DNA-damaging chemotherapeutic agents. 7-Methylguanine possesses attractive predictable pharmacokinetics and an adverse-effect profile and may be considered as a new additive to chemotherapeutic treatment.
| S-EPMC4947994 | biostudies-literature
Project description:Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated "parthanatos" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD(+) and energetic collapse, which have been thought to be caused by the consumption of cellular NAD(+) by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD(+) depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD(+) depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD(+) with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.
| S-EPMC4104885 | biostudies-literature
Project description:Excessive activation of poly (ADP-ribose) polymerase (PARP) contributes to ischemic acute kidney injury (AKI). PARP inhibition has been shown to be beneficial in renal ischemia-reperfusion injury (IRI) in the early phase, but its role in the repair process remains unclear. The effects of JPI-289, a novel PARP inhibitor, during the healing phase after renal IRI were investigated. IRI was performed on 9-week-old male C57BL/6 mice. Saline or JPI-289 100 mg/kg was intraperitoneally administered once at 24 h or additionally at 48 h after IRI. Hypoxic HK-2 cells were treated with JPI-289. Renal function and fibrosis extent were comparable between groups. JPI-289 treatment caused more prominent tubular atrophy and proinflammatory intrarenal leukocyte phenotypes and cytokines/chemokines changes at 12 weeks after unilateral IRI. JPI-289 treatment enhanced gene expressions associated with collagen formation, toll-like receptors, and the immune system in proximal tubules and endothelial cells after IRI. JPI-289 treatment at 3 or 6 h after hypoxia facilitated proliferation of hypoxic HK-2 cells, whereas further treatment after 24 h suppressed proliferation. Delayed inhibition of PARP after renal IRI did not facilitate the repair process during the early healing phase but rather may aggravate renal tubular atrophy during the late healing phase in ischemic AKI.
| S-EPMC10761972 | biostudies-literature
Project description:The urokinase plasminogen activator (uPA) system is a complex regulator of extracellular proteolysis which is involved in various physiological and pathological processes. The major components of this system are the serine protease uPA, two inhibitors PAI-1 and PAI-2, and the receptor uPAR. It has been previously shown by several groups that the uPA system has an important role in cancer progression and therefore its possible prognostic and therapeutic value has been evaluated. The aim of this study is to tackle the role of poly(ADP-ribosyl)ation in the induction of uPA activity in a glioblastoma cell line, A1235. This cell line is sensitive to alkylation damage and is a model for drug treatment. The components of the uPA system and the level of DNA damage were analyzed after alkylation agent treatment in combination with poly(ADP-ribose)polymerase-1 (PARP-1) inhibition. Here we show that the increase in uPA activity results from the net balance change between uPA and its inhibitor at mRNA level. Further, PARP-1 inhibition exerts its influence on uPA activity through DNA damage increase. Involvement of several signaling pathways, as well as cell specific regulation influencing the uPA system are discussed.
| S-EPMC4960128 | biostudies-literature