PARP inhibitors: New partners in the therapy of cancer and inflammatory diseases

Peralta-Leal, Andreína; Rodríguez-Vargas, José Manuel; Aguilar-Quesada, Rocío; Rodríguez, María I.; Linares, José Luis; Almodóvar, Mariano Ruiz de; Oliver, F. Javier

doi:10.1016/j.freeradbiomed.2009.04.008

Cited by 168 publications

(155 citation statements)

References 156 publications

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“…In fact, PARP inhibition or PARP-1 depletion has provided marked protection in most animal models of inflammation with many of them being dependent on T cell functions [45,57]. The defect of PARP-2 seems to be associated with a narrower spectrum of diseases in murine models.…”

Section: The Role Of Parp-2 In Thymopoesis and Inflammatory Regulationmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

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Section: The Role Of Parp-2 In Thymopoesis and Inflammatory Regulationmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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“…Another evolving approach to enhancing the effectiveness of drugs and/or radiation that damage DNA or interfere with the cell cycle is to target DNA-damage defense mechanisms. [10][11][12] For example, inhibition of wild-type p53 with a small molecule inhibitor, cyclic pifithrin-alpha p-nitro, enhances cell killing of glioblastoma multiforme (GBM) cells in vitro and in vivo by temozolomide (TMZ), a DNA-methylating drug without increasing toxicity. 13 As expected, however, the two drug combination is no more effective than TMZ alone in cells lacking wildtype p53.…”

Section: Enhancement Of Cancer Therapymentioning

confidence: 99%

“…Another strategy for enhancing the effectiveness of chemotherapy is inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 12 in cancers deficient in repair of doublestrand DNA breaks (DSBs). 19 PARP is needed for repair of single-strand breaks (SSBs).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome

Zhuang

Lü²,

Lonser³

et al. 2009

Cell Cycle

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Despite improvements in the therapeutic efficacy of rationally designed cancer treatment regimens, most cancers remain incurable once spread beyond their sites of origin. Failure to achieve sustained control or eradication of cancers arises in large part because a subpopulation of quiescent "cancer stem cells" is insensitive to drugs targeting cell growth and replication and because defense mechanisms critical to survival of the normal cell also protect the cancer cell from cytotoxic injury. Global alteration of signal transduction by inhibition of serine/threonine dephosphorylation has recently been shown to markedly potentiate cancer cell killing by the DNA-methylating drug, temozolomide. Inhibition of the multifunctional protein phosphatase 2A appears to drive quiescent cancer cells into cycle and simultaneously inhibits cycle arrest, permitting cancer cell entry into mitosis despite the presence of chemotherapy induced DNAdamage. Absence of toxicity in animal models suggests that multi-site mutations in pathways regulating cell cycle in cancer cells make them more vulnerable than normal cells to large changes in the balance of phosphorylation-regulated signaling. Global modulation of the serine-threonine phospho-proteome may be a general method for enhancing the effectiveness of cytotoxic cancer therapy.

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“…PARP1 inhibition mitigates morbidity and mortality in multiple inflammatory and autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, septic shock, ischemic stroke, acute pancreatitis, asthma, and inflammatory bowel diseaselike colitis (5). Genetic ablation or pharmacological inhibition of PARP1 reduces the biological and physical manifestations of experimental colitis; Il-10 Ϫ/Ϫ mice treated with a PARP1 inhibitor (3-aminobenzamide) show a significant reduction in proinflammatory cytokine production associated with reduced intestinal permeability (6).…”

mentioning

confidence: 99%

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

Larmonier

Shehab

Laubitz

et al. 2016

Journal of Biological Chemistry

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Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate and participate in the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator cytokines, chemokines, and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury and on the gut microbiome composition. were protected from dextran-sulfate sodium-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. PARP1 deficiency was also associated with a modulation of the colonic microbiota (increases relative abundance of Clostridia clusters IV and XIVa) and a concomitant increase in the frequency of mucosal CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. The protective effects conferred by Parp1 deletion were lost in Rag2

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PARP inhibitors: New partners in the therapy of cancer and inflammatory diseases

Cited by 168 publications

References 156 publications

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

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