PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

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Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

应用Meta分析有效估计人群归因危险度百分比的探讨

人群归因危险度百分比 (populationattributableriskproportion ,PARP)是总体人群中某种疾病归因于某种因素的暴露所引起的发病 (死亡 )占全部发病 (死亡 )的百分比 ,反映该因素所引起的发病 (死亡 )占全部发病 (死亡 )的比重。通过PARP可了解各危险因素对人群中某疾病的发病所产生的影响 ,亦即消除某危险因素后 ,所产生的对预防该疾病的效果将占有多大比重。它能够为卫生政策的制订提供依据 ,有着重要的公共卫生的实际意义。目前常用的估计PARP的方法有两种 :一种是利用全国人群抽样调查获得的人群总暴露率来估计 ;另一种是利用某地区…     

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.     

New opportunities in chemosensitization and radiosensitization: modulating the DNA-damage response

Many current cancer treatments, including certain classes of chemotherapeutics and radiation, induce cytotoxicity by damaging DNA. However, many cancers are resistant to these therapies, which represents a significant challenge in the clinic. Thus, modulating DNA-damage responses to selectively enhance the sensitivity of cancer cells to these therapies is highly desirable. When DNA damage is detected, DNA checkpoint mechanisms are activated to halt cells at various phases of the cell cycle. Simultaneously, DNA-damage sensors transduce signals to activate DNA-repair mechanisms via de novo expression or post-translational modification of enzymes required for DNA repair. p53 is the major player in a checkpoint that arrests cells at the G₁/S boundary, while checkpoint kinase (Chk)1 is critical for the G₂/M checkpoint and also the S checkpoint that prevents cell cycle progression after replication defects (intra-S-phase checkpoint) or S/M uncoupling (S/M checkpoint). Poly(ADP-ribose) polymerase is involved in sensing DNA single-strand breaks and inducing DNA repair via poly(ADP-ribosyl)ating various DNA-binding and DNA-repair proteins. In this review, strategies for implementing small-molecule inhibitors of poly(ADP-ribose) polymerase and Chk1, which are emerging as potential adjuncts to current therapies, are discussed.     

Poly(ADP-ribose) polymerase inhibitors in the prevention of neuronal cell death

Poly(ADP-ribose) polymerase is a nucleic enzyme that promotes energy-dependent repair of DNA, thus helping to protect against DNA fragmentation. Overactivation of PARP, for example in the context of apoptosis, may contribute to neuronal cell death. This article briefly reviews claims for PARP inhibitors as agents for the prevention of neuronal cell death, registered in the period 1998 – December 2001. Biological data are sparse in these patents, few claims are backed by in vitro biochemical data and fewer still with in vivo animal model data. The latter have used animal models of ischaemia rather than of neurodegeneration. The place of PARP inhibitors as a clinical therapy to prevent neuronal cell death remains to be determined.     

PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS

Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (¹H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD⁺) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. ¹H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD⁺ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD⁺ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD⁺ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD⁺ depletion caused by temozolomide treatment. The ¹H‐MRS results show that NAD⁺ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD⁺ would be valuable.