Poly(ADP-ribose) polymerase inhibition in cancer therapy: are we close to maturity?

Papeo, Gianluca; Forte, Barbara; Orsini, Paolo; Perrera, Claudia; Posteri, Helena; Scolaro, Alessandra; Montagnoli, Alessia

doi:10.1517/13543770903215883

Cited by 34 publications

(28 citation statements)

References 79 publications

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“…Although these findings point to the interplay among NAD, PARP-1, and SIRT-1 as a target to improve mitochondrial dysfunction, their relevance to mitochondrial disorders and related encephalopathy remains elusive. Remarkably, PARP-1 inhibitors have been proven to have therapeutic efficacy in different models of human disorders [24], and have recently reached the clinical arena, showing a safety profile in patients with different neoplasms [25,26].…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

et al. 2014

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Mitochondrial disorders are deadly childhood diseases for which therapeutic remedies are an unmet need. Given that genetic suppression of the nuclear enzyme poly (adenine diphosphate-ribose) polymerase(PARP)-1 improves mitochondrial functioning, we investigated whether pharmacological inhibition of the enzyme affords protection in a mouse model of a mitochondrial disorder. We used mice lacking the Ndufs4 subunit of the respiratory complex I (Ndufs4 knockout [ KO] mice); these mice undergo progressive encephalopathy and die around postnatal day 50. Mice were treated daily with the potent PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,Ndimethylamino)acetamide hydrochloride (PJ34); neurological parameters, PARP activity, and mitochondrial homeostasis were evaluated. We found that mice receiving N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride from postnatal day 30 to postnatal day 50 show reduced neurological impairment, and increased exploratory activity and motor skills compared with vehicle-treated animals. However, drug treatment did not delay or reduce death. We found no evidence of increased PARP activity within the brain of KO mice compared with heterozygous, healthy controls. Conversely, a 10-day treatment with the PARP inhibitor significantly reduced basal poly(ADP-ribosyl)ation in different organs of the KO mice, including brain, skeletal muscle, liver, pancreas, and spleen. In keeping with the epigenetic role of PARP-1, its inhibition correlated with increased expression of mitochondrial respiratory complex subunits and organelle number. Remarkably, pharmacological targeting of PARP reduced astrogliosis in olfactory bulb and motor cortex, but did not affect neuronal loss of KO mice. In light of the advanced clinical development of PARP inhibitors, these data emphasize their relevance to treatment of mitochondrial respiratory defects.

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Section: Introductionmentioning

confidence: 99%

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

et al. 2014

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“…PARP-1 is activated by DNA damage and is primarily responsible for initiating the repair of single-strand DNA breaks via a base excision repair (BER) pathway. When coadministered with DNAdamaging chemotherapeutic agents, PARP inhibitors could potentiate the efficacy of these agents by preventing the repair of the damaged DNA through BER (Papeo et al, 2009;Rouleau et al, 2010). Thus, PARP inhibitors could be developed as chemosensitizers of DNAdamaging agents.…”

Section: Introductionmentioning

confidence: 99%

“…PARP inhibitors have also demonstrated single agent effects in selected genetic backgrounds such as tumors with defects in the breast cancer-associated genes (BRCA-1 and -2), the homologous recombination DNA repair regulators. PARP inhibition blocks the BER pathway and results in "synthetic lethality" effects toward homologous recombination-deficient tumors (Papeo et al, 2009;Rouleau et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Li¹,

Delzer²,

Voorman³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The Veliparib absorption was high. Dosed radioactivity was widely distributed in rat tissues. The majority of drug-related material was excreted in urine as unchanged drug (approximately 54, 41, and 70% of the dose in rats, dogs, and humans, respectively). A lactam M8 and an amino acid M3 were two major excretory metabolites in animals. In the circulation of animals and humans, veliparib was the major drug-related component, and M8 was one of the major metabolites. Monooxygenated metabolite M2 was significant in the rat and dog, and M3 was also significant in the dog. Veliparib biotransformation occurred on the pyrrolidine moiety via formation of a lactam, an amino acid, and an N-carbamoyl glucuronide, in addition to oxidation on benzoimidazole carboxamide and sequential glucuronidation. In vitro experiments using recombinant human cytochrome P450 (P450) enzymes identified CYP2D6 as the major enzyme metabolizing veliparib with minor contributions from CYP1A2, 2C19, and 3A4. Veliparib did not inhibit or induce the activities of major human P450s. Veliparib was a weak P-glycoprotein (P-gp) substrate, showing no P-gp inhibition. Taken together, these studies indicate a low potential for veliparib to cause clinically significant P-gp or P450-mediated drug-drug interactions (DDIs). Overall, the favorable dispositional and DDI profiles of veliparib should be beneficial to its safety and efficacy.

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“…The competitive PARP inhibitors, most of which are PARP1/2 inhibitors, play a leading role in current drug development programs. Such inhibitors are designed to mimic nicotinamide and compete for the catalytic domain of PARPs [5,[45][46][47][48] . For PARP1 inhibitors, as yet, more than 30 scaffolds have been reported, including isoquinolinones, dihydroisoquinolinones, quinazolinediones, quinazolinones, benzimidazole and benzoxazole carboxamides (detailed in the comprehensive review by Ferraris DV) [5] .…”

Section: Parp Inhibitors As Cancer Therapeuticsmentioning

confidence: 99%

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Yang

Miao

2010

Acta Pharmacol Sin

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The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.

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Poly(ADP-ribose) polymerase inhibition in cancer therapy: are we close to maturity?

Cited by 34 publications

References 79 publications

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

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