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Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors.

ABSTRACT: Poly(ADP-ribose) polymerases are a family of DNA-dependent nuclear enzymes catalyzing the transfer of ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide to a variety of target proteins. Although they have been considered as resident nuclear elements of the DNA repair machinery, recent works revealed a more intricate physiologic role of poly(ADP-ribose) polymerases with numerous extranuclear activities. Indeed, poly(ADP-ribose) polymerases participate in fundamental cellular processes like chromatin remodelling, transcription or regulation of the cell-cycle. These new insight into the physiologic roles of poly(ADP-ribose) polymerases widens the range of human pathologies in which pharmacologic inhibition of these enzymes might have a therapeutic potential. Here, we overview our current knowledge on extranuclear functions of poly(ADP-ribose) polymerases with a particular focus on the mitochondrial ones and discuss potential fields of future clinical applications.

SUBMITTER: Cseh AM

PROVIDER: S-EPMC5564845 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors.

Cseh Anna Mária AM Fábián Zsolt Z Sümegi Balázs B Scorrano Luca L

Oncotarget 20170701 30

Poly(ADP-ribose) polymerases are a family of DNA-dependent nuclear enzymes catalyzing the transfer of ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide to a variety of target proteins. Although they have been considered as resident nuclear elements of the DNA repair machinery, recent works revealed a more intricate physiologic role of poly(ADP-ribose) polymerases with numerous extranuclear activities. Indeed, poly(ADP-ribose) polymerases participate in fundamental cellular proc ...[more]

PMID: 28430591

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Project description:BackgroundMore patients with ovarian cancer are being treated with poly(adenosine diphosphate-ribose) polymerase inhibitors because regulatory agencies have granted these drugs new approvals for a variety of treatment indications. However, poly(adenosine diphosphate-ribose) polymerase inhibitors are expensive. When administered as a maintenance therapy, these drugs may be administered for months or years. How much of this cost patients experience as out-of-pocket spending is unknown.ObjectiveThis study aimed to estimate the out-of-pocket spending that patients experience during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment and to characterize which healthcare services account for that spending.Study designA retrospective cohort study was performed with a sample of patients with ovarian cancer treated between 2014 and 2017 with olaparib, niraparib, or rucaparib. Patients were identified using MarketScan, a health insurance claims database. All insurance claims during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment were collected. The primary outcome variable was the patients' out-of-pocket spending (copayment, coinsurance, and deductibles) during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment for the medication itself. Other outcomes of interest included out-of-pocket spending for other healthcare services, the types and frequency of other healthcare services used, health plan spending, the estimated proportion of patients' household income used each month for healthcare, and patients' out-of-pocket spending immediately before poly(adenosine diphosphate-ribose) polymerase inhibitor treatment.ResultsWe identified 503 patients with ovarian cancer with a median age of 55 years (interquartile range, 50-62 years); 83% of those had out-of-pocket spendings during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment. The median treatment duration was 124 days (interquartile range, 66-240 days). The mean out-of-pocket spending for poly(adenosine diphosphate-ribose) polymerase inhibitors was $305 (standard deviation, $2275) per month. On average, this accounted for 44.8% (standard deviation, 34.8%) of the patients' overall monthly out-of-pocket spending. The mean out-of-pocket spending for other healthcare services was $165 (standard deviation, $769) per month. Health plans spent, on average, $12,661 (standard deviation, $15,668) per month for poly(adenosine diphosphate-ribose) polymerase inhibitors and $7108 (standard deviation, $15,254) per month for all other healthcare services. The cost sharing for office visits, laboratory tests, and imaging studies represented the majority of non-poly(adenosine diphosphate-ribose) polymerase inhibitor treatment out-of-pocket spending. The average amount patients paid for all healthcare services per month during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment was $470 (standard deviation, $2407), which was estimated to be 8.7% of the patients' monthly household income. The mean out-of-pocket spending in the 12 months before poly(adenosine diphosphate-ribose) polymerase inhibitor treatment was $3110 (standard deviation, $6987).ConclusionPatients can face high out-of-pocket costs for poly(adenosine diphosphate-ribose) polymerase inhibitors, although the sum of cost sharing for other healthcare services used during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment is often higher. The spending on healthcare costs consumes a large proportion of these patients' household income. Patients with ovarian cancer experience high out-of-pocket costs for healthcare, both before and during poly(adenosine diphosphate-ribose) polymerase inhibitor treatment.

Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a severe form of lung injury that frequently occurs during pneumonia and sepsis. Lung inflammation in ARDS patients may have deleterious effects on remote organs such as the kidney. The nuclear enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) enhances the nuclear factor (NF)-?B-dependent transcription of inflammatory cytokines. This study was conducted to elucidate two questions: first, whether the activation of PARP and NF-?B mediates the renal inflammation secondary to the lipopolysaccharide (LPS)-induced acute lung inflammation; second, whether a PARP inhibitor, 3-aminobenzamide (3-AB), attenuates lung and kidney inflammation by inhibiting NF-?B-dependent proinflammatory cytokines.MethodsMale Sprague-Dawley rats were anesthetized, ventilated, and divided into three groups; a control group (n?=?8); an LPS group (n?=?12) intratracheally instilled with LPS (16 mg/kg), and an LPS?+?3-AB group (n?=?12) given the same dose of LPS by the same method followed by an intravenous injection of 3-AB (20 mg/kg). Hemodynamics, arterial blood gas, and the plasma levels of lactate, creatinine and potassium were measured at 0,1,2,3, and 4 h after treatment. The lung wet/dry ratio was measured at 4 h. The mRNA expression of tumor necrosis factor (TNF)-?, interleukin (IL)-1? and IL-6 in the lung and kidney were measured by TaqMan real-time PCR. PARP and NF-?B in the lung and kidney were histologically examined by immunostaining and assigned expression scores.ResultsLPS induced metabolic acidosis, hypotension, hypoxemia, increased the lung wet/dry ratio, increased the plasma levels of creatinine and potassium, and increased the cytokine mRNA expressions in the lung and kidney. All of these effects were associated with strong expression of PARP and NF-?B. Treatment with 3-AB prevented the LPS-induced metabolic acidosis and hypotension, reduced the plasma levels of lactate, creatinine and potassium, reduced the cytokine mRNA expressions, reduced the expression of PARP and NF-?B, improved pulmonary edema and oxygenation and preserved renal function.ConclusionsThe PARP inhibition attenuated lung-kidney crosstalk induced by intratracheal LPS instillation, partly via an inhibition of NF-?B dependent proinflammatory cytokines.

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Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors.

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Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors.

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