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Simple Summary: Poly ADP-ribose polymerase inhibitors (PARPis) can be used in men with advanced prostate cancer. Unfortunately, this class of therapeutics has demonstrated the risk of developing hematological adverse events. We conducted a systematic review and meta-analysis of several PARPi clinical trials to further evaluate the incidence of anemia, thrombocytopenia, and neutropenia adverse events in prostate cancer patients. We found that this treatment is significantly associated with hematologic suppression. Further stratification suggests differences may exist between PARPis within this class of therapy. Background: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. Objective: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. Study Methodology: A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews—Cochrane were queried from inception to 9 June 2023. The Mantel–Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. Results: The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37–4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97–10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60–6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06–11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80–10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77–17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. Conclusion: PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient–physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs. [ABSTRACT FROM AUTHOR]

[Display omitted] Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition. [ABSTRACT FROM AUTHOR]

Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

Recent genome-wide association studies of Huntington's disease (HD) primarily highlighted genes involved in DNA damage repair mechanisms as modifiers of age at onset and disease severity, consistent with evidence that more DNA repair genes are being implicated in late age-onset neurodegenerative diseases. This provides an exciting opportunity to advance therapeutic development in HD, as these pathways have already been under intense investigation in cancer research. Also emerging are the roles of other polyglutamine disease proteins in DNA damage repair mechanisms. A potential universal trigger of oxidative DNA damage shared in these late age-onset diseases is the increase of reactive oxygen species (ROS) in human aging, defining an age-related mechanism that has defied other hypotheses of neurodegeneration. We discuss the potential commonality of DNA damage repair pathways in HD and other neurodegenerative diseases. Potential targets for therapy that may prove beneficial across many of these diseases are also identified, defining nodes in the ataxia telangiectasia-mutated (ATM) complex, mismatch repair, and poly ADP-ribose polymerases (PARPs). [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP‐ribose polymerase‐1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma. Methods: We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome‐sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines. Results: Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA‐damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV‐negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression. Conclusion: Based on PARP1 overexpression, DNA‐damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma. [ABSTRACT FROM AUTHOR]

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent anti-proliferative activity against those human cancer cell lines and compound 5r showed the most potent biological activity against HepG2 cells with an IC50 value of 10.56 ± 1.14 µM. In addition, bioassays showed that compound 5r induced time-dependent and dose-dependent cleavage of poly ADP-ribose polymerase (PARP), and also induced a dose-dependent increase in caspase-3 and caspase-8 activity, but had little effect on caspase-9 protease activity in HepG2 cells. These results provide evidence that 5r-induced apoptosis in HepG2 cell is caspase-8-dependent. [ABSTRACT FROM AUTHOR]

The goal of this study was to assess the expression of poly ADP-ribose polymerase (PARP) and apoptosis-inducing factor (AIF) in the hippocampal CA1 region, and to find out whether nigranoic acid treatment exhibits protective effects on brain through PARP/AIF signaling pathway in cerebral ischemia-reperfusion animal model. Rats were randomly divided into three groups: Sham-surgery, ischemia-reperfusion, and nigranoic acid-treated. Rat models of middle cerebral artery occlusion were prepared using a way of thread occlusion. Rats in the nigranoic acid group were administered with 1 mg/kg intragastric nigranoic acid 6 and 2 h before brain ischemia, respectively. Following reperfusion, samples were collected at different time-points (6, 24, and 72 h) and each group was further divided into three subgroups. Apoptosis was measured using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling method. The protein expression levels of AIF and PARP were detected using Western blot and AIF mRNA quantity was evaluated using the reverse transcription-polymerase chain reaction. Apoptosis, levels of AIF and PARP protein expression, and levels of AIF mRNA expression were significantly increased in the ischemia-reperfusion group compared with the sham-surgery group. However, apoptosis and the expression levels of AIF protein, PARP protein, and AIF mRNA at different time-points were significantly decreased in the nigranoic acid-treated group compared with the model group. We can judge that nigranoic acid has a strong protective effect on rat cerebral ischemia-reperfusion injury, and acts by downregulating nerve cell apoptosis by preventing the overactivation of PARP and AIF nuclear translocation. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dysregulation of mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of PD. However, the underlying mechanism is incompletely elucidated. Here, we show that PD mimetics (6-hydroxydopamine, N-methyl-4-phenylpyridine or rotenone) suppressed phosphorylation of mTOR, S6K1 and 4E-BP1, reduced cell viability, and activated caspase-3 and PARP in PC12 cells and primary neurons. Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR-mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death. Furthermore, we found that the inhibition of mTOR signaling contributing to neuronal cell death was attributed to suppression of Akt and activation of AMPK. This is supported by the findings that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPKα with compound C partially attenuated inhibition of phosphorylation of mTOR, S6K1 and 4E-BP1, activation of caspase-3, and neuronal cell death triggered by the PD toxins. The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that proper co-manipulation of AMPK/Akt/mTOR signaling may be a potential strategy for prevention and treatment of PD. [Copyright &y& Elsevier]

Abstract: Human cholangiocarcinoma (CCA) is a chemoresistant bile duct carcinoma with a poor prognosis. Conventional chemotherapy and radiotherapy have not been reported to be effective in improving long-term survival. Mycoepoxydiene (MED), a polyketide isolated from the marine fungal strain Diaporthe sp. HLY-1 associated with mangroves, has been shown to be an agent capable of inducing apoptosis in MCF-7 and Hela cell lines. However, little is known about the effect of MED in CCA. Herein, we investigated the effect of MED on CCA cells proliferation and invasion. The results demonstrated that MED induced apoptosis in CCA cells such as SK-ChA-1 and Mz-ChA-1 through inhibiting the expression of anti-apoptotic proteins such as Bcl-XL and Bcl-2, two targets of NF-κB. In addition, MED significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CCA cells invasion in a dose-dependent manner by reducing the expression of matrix metalloelastase 9 (MMP-9). Moreover, MED inhibited TPA-induced NF-κB activation via blocking phosphorylation and degradation of IκBα and phosphorylation of IκB kinase (IKK). MED had no effect on the activation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, which are also involved in regulating the MMP-9 expression. Collectively, MED significantly suppressed proliferation and invasion of CCA cells such as SK-ChA-1 and Mz-ChA-1, suggesting that MED is a potential lead compound for the development of novel drugs for therapy of CCA. [Copyright &y& Elsevier]

Highlights: [•] S-Allylmercaptocysteines (CySSR) act synergistically with sodium selenite to mediate apoptosis in breast cancer cells. [•] The major CySSRs derived from onion and garlic are similarly potent, but act preferentially on different cellular targets. [•] The proposed mechanism is that cells import and reduce CySSR, then export thiols to reduce selenite to the cytotoxic H2Se. [ABSTRACT FROM AUTHOR]

Abstract: A series of new, water-soluble phenyl N-mustard-benzenealkylamide conjugates containing hydrophilic ω-dialkylaminoalkylamide or ω-cyclic aminoalkylamide moieties were synthesized via a bioisostere approach. These compounds have a broad spectrum of antitumor activity against a panel of human tumor cell lines. Of these derivatives, compound 18b effectively suppressed the growth of colon cancer (HCT-116), prostate cancer (PC3), and lung cancer (H460) xenografts. The growth of HCT-116 xenografts was almost completely suppressed when co-treated with compound 18b and 5-fluorouracil. Furthermore, compound 18b can induce DNA cross-linking and cell-cycle arrest at the G2/M phase. Early preclinical studies, including pharmacokinetics in rats, inhibition of the hERG, and 14 days of acute intravenous injection toxicity, suggest that compound 18b is a promising candidate for further preclinical studies. [Copyright &y& Elsevier]

Abstract: The present study was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against CCl4-induced hepato-toxicity in mice. The mice were orally administrated with TSDN for seven days and then given CCl4 (0.3%, 10ml/kg i.p.). The results showed that TSDN significantly attenuated the activities of ALT and AST, consistent with hematoxylin–eosin staining. The ALP levels and relative liver weight were significantly decreased by TSDN compared with model group. Moreover, TSDN dramatically decreased MDA, iNOS and NO levels, while the levels of GSH, GSH-Px and SOD were increased. Further investigations showed that TSDN inhibited CCl4-induced metabolic activation and CYP2E1 expression, down-regulated the levels of MAPKs phosphorylation, NF-κB, HMGB1, COX-2 as well as effectively suppressed the expressions of Caspase-3, Caspase-9, PARP and Bak. Quantitative real-time PCR assay demonstrated that TSDN obviously decreased the gene expressions of TNF-a, IL-1β, IL-6, IL-10, Fas, FasL, Bax as well as modulated Bcl-2 mRNA level. This is the first time to report the protective actions of the TSDN against CCl4-induced liver damage in mice through suppression of inflammation and apoptosis. This natural product should be developed as a new drug for treatment of liver injury in future. [Copyright &y& Elsevier]

Highlights: [•] Verapamil (Ver) and gambogic acid (GA) synergistically induced cytotoxicity (count:67). [•] Ver enhanced GA-induced proteasome inhibition, ER stress and caspase system (count:66). [•] Ver and GA synergistically enhanced ROS (reactive oxygen species) generation (count:67). [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Tripterygium hypoglaucum (levl.) Hutch (Celastraceae) (THH) root is a traditional Chinese medicinal herb commonly used for treating autoimmune diseases and cancer. Alkaloid is one of the most bioactive components of THH extract. To evaluate the in vitro and in vivo antitumor properties of the total alkaloids of THH (THHta). Materials and methods: THHta was extracted in pilot-scale. HCT116 cells were chose to establish human colon cancer xenograft model. The in vitro anti-tumor activity of THHta was tested by Cell malignant transformation test, Soft agar colony formation assay and MTT assay. The in vivo anti-tumor effect of THHta was confirmed by xenograft mouse model. THHta-induced apoptosis was examined by flow cytometry. The levels of apoptosis-related proteins were investigated by Western blot. Results: TPA-induced cell transformation was significantly inhibited by THHta in JB6 Cl41 cells. THHta inhibits the growth of colon cancer cells in vitro in a significant dose-dependent manner. Compared to the control set, i.p. administration of THHta to xenograft mice significantly reduced both tumor weight and volume. Apoptosis induction of THHta was mediated by activation of caspase-3, PARP and inhibiting of Bcl-2, Bcl-xL and XIAP. Conclusion: THHta was effective in inhibiting tumor growth both in vitro and in vivo at less toxic concentrations by inducing apoptosis which suggested it could be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Highlights: [•] Armillarikin is a compound isolated from medicinal mushroom Armillaria mellea. [•] Armillarikin induces apoptosis in human K562, U937 and HL-60 leukemia cells. [•] Armillarikin increases production of intracellular ROS in human leukemia cells. [•] ROS scavengers attenuate armillarikin-induced apoptosis. [•] Armillarikin-induced apoptosis is mediated by ROS production. [Copyright &y& Elsevier]

Abstract: Bifunctional DNA cross-linking agents are widely used as chemotherapeutic agents in clinics. The advance in the development of these agents as potential antitumor agents has generated various types of bis(hydroxymethyl)pyrrole analogs. In order to develop highly effective anticancer agents, it is necessary to understand the chemophysical properties, structure–activity relationships, therapeutic potency, toxicity/safety, and pharmacokinetics of these DNA cross-linking agents. This review presents an overview of the recent advances in developing various types of bis(hydroxymethyl)pyrrole analogs with potential antitumor activity to provide more information for future drug design and strategies for combination chemotherapy. The rational drug design, chemical syntheses, antitumor activity, mechanism of action, and development of combined chemotherapy regimens, including a DNA repair inhibitor, are discussed. [Copyright &y& Elsevier]

Abstract: Antibacterial peptides (ABPs) with cancer-selective toxicity have received much more attention as alternative chemotherapeutic agents in recent years. However, the basis of their anticancer activity remains unclear. The modification of cell surface glycosylation is a characteristic of cancer cells. The present study investigated the effect of glycosylation, in particular sialic acid, on the anticancer activity of ABPs. We showed that aurein 1.2, buforin IIb and BMAP-28m exhibited selective cytotoxicity toward MX-1 and MCF-7 breast cancer cells. The binding activity, cytotoxicity and apoptotic activity of ABPs were enhanced by the presence of O-, N-glycoproteins, gangliosides and sialic acid on the surface of breast cancer cells. Among N-, O-glycoproteins and ganglioside, O-glycoproteins almost had the strongest effect on the binding and cytotoxicity of the three peptides. Further, up-regulation of hST6Gal1 in CHO-K1 cells enhanced the susceptibility of cells to these peptides. Finally, the growth of MX-1 xenograft tumors in mice was significantly suppressed by buforin IIb treatment, which was associated with induction of apoptosis and inhibition of vascularization. These data demonstrate that the three peptides bind to breast cancer cells via an interaction with surface O-, N-glycoproteins and gangliosides. Sialic acids act as key glycan binding sites for cationic ABP binding to glycoproteins and gangliosides. Therefore, glycosylation in breast cancer cells plays an important role in the anticancer activity of ABPs, which may partly explain their cancer-selective toxicity. Anticancer ABPs with cancer-selective cytotoxicity will be promising candidates for anticancer therapy in the future. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to the complicated molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on anti-HCC compounds derived from CHM, especially their underlying pharmacological mechanisms. Materials and methods: A systematic search of anti-HCC compounds from CHM was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic databases (Wanfang and CNKI database). Results: In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed. Conclusion: Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM. [Copyright &y& Elsevier]

Highlights: [•] Three new sesquiterpenes were isolated from Celastrus paniculatus. [•] One of them suppresses proliferation of breast cancer cells. [•] It also targets signaling pathways mediated by Akt, NF-κB, p53, and ROS. [•] Its mode of mechanism underlies its effect on apoptosis and autophagy. [Copyright &y& Elsevier]

Highlights: [•] To investigate I. suffruticosa extracts on expression of GSTP and NQO1 in hepatocytes. [•] Suffruticosa extracts increased GSTP and NQO1 levels and GSTP promoter activity in hepatocyte. [•] Suffruticosa extracts up-regulated binding affinity of Nrf2 with GPEI and ARE activation. [•] ERK inhibitor abolished I. suffruticosa extracts induced GSTP and NQO-1 expression. [•] Suffruticosa extracts increased GSH levels in mouse liver, RBC and hepatocytes. [ABSTRACT FROM AUTHOR]

Highlights: [•] H2O2 treatment reduced neurite outgrowth in differentiated SH-SY5Y cells time-dependently. [•] H2O2 modulated autophagic factors including LC3B, Atg7, and Atg12. [•] H2O2 increased apoptotic factors including Bax/Bcl-2 ratio, caspase-3, and PARP. [•] Inhibition of autophagy by 3MA increased Aβ levels in human neuroblastoma cells exposed to H2O2. [Copyright &y& Elsevier]

Abstract: Apoptosis is a critical defense mechanism against the formation and progression of cancer and exhibits distinct morphological and biochemical traits. Targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. Peptides from marine organisms have become important sources in the discovery of antitumor drugs, especially when modern technology makes it more and more feasible to collect organisms from seas. This primer summarizes several marine peptides, based on their effects on apoptotic signaling pathways, although most of these peptides have not yet been studied in depth for their mechanisms of action. Novel peptides that induce an apoptosis signal pathway are presented in association with their pharmacological properties. [Copyright &y& Elsevier]

Highlights: [•] The functional role of oncogenic Src and Ras in curcumin sensitivity was investigated. [•] Activated Src and Ras do not confer resistance to curcumin. [•] Antitumor activity is mediated by apoptosis induction in Src-driven cells. [•] Cell cycle arrest at G2/M is responsible for growth inhibition of Ras-driven cells. [•] These data provide a treatment rationale for Src- or Ras-activated human cancer. [ABSTRACT FROM AUTHOR]

N-[3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)phenyl]-4-(morpholin-4-yl) butanamide methanesulfonate monohydrate (ONO-1924H) is a novel inhibitor of poly ADP-ribose polymerase (PARP). In this study, we examined the effects of ONO-1924H on cytotoxicity induced by hydrogen peroxide in PC12 cells in vitro and cerebral damage and neurological deficits induced by middle cerebral artery (MCA) thrombus occlusion in vivo in rat. In the in vitro cytotoxicity assay, exposure to 0.5 mmol/L hydrogen peroxide induced cell death in differentiated PC12 cells. ONO-1924H, a PARP inhibitor (Ki=0.21 μmol/L), reduced cell death in a concentration-dependent manner that was correlated with inhibition of PARP activation. A 50% reduction in cell death (EC50) was achieved with 2.4 μmol/L ONO-1924H. In the MCA occlusion model, ONO-1924H was injected intravenously at doses of 3, 10 and 30 mg/kg/h for 3 h, and cerebral damage and neurological deficits were estimated 24 h after MCA occlusion. ONO-1924H treatment led to a significant decrease in cerebral damage in the 10 mg/kg/h-treated group (P < 0.05) and the 30 mg/kg/h-treated group (P < 0.01). Further, ONO-1924H at doses of 30 mg/kg/h significantly (P < 0.05) improved neurological deficits. These findings suggest that the novel PARP inhibitor, ONO-1924H, affords effective neuroprotection and is a useful therapeutic candidate for the treatment of ischemic stroke. [Copyright &y& Elsevier]

Latent membrane protein 1 (LMP1) encoded by Epstein–Barr virus (EBV) is a membrane protein that activates multiple signaling pathways and transcription factors, including NF-κB. Our recent report demonstrated that expression of LMP1 induced programmed cell death in an NF-κB-dependent manner. In this study, we demonstrate that a variant CAO-LMP1 derived from EBV-infected nasopharyngeal carcinoma (NPC) does not induce cell death unlike the prototype B95.8-LMP1, although both types of LMP1 show NF-κB activation to a similar extent. Studies with chimeric or mutated proteins identified two amino acids in the transmembrane domain, which are commonly substituted in NPC-derived LMP1 variants, being critical for cell death induction by B95.8-LMP1. Furthermore, we show that the B95.8 transmembrane domain co-operates with NF-κB to trigger cell death program. Thus, our results reveal a particular feature of the transmembrane domain of tumor-derived CAO-LMP1 and suggest its possible contribution to the pathogenesis of NPC. [Copyright &y& Elsevier]

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a central role in controlling the cellular response to ionizing radiation and other DNA-damaging agents. ATM is a 3056 amino acid polypeptide that is present in low abundance in the nucleus of human cells. Here, we describe the purification and characterization of ATM from the nuclear fraction of HeLa cells. Microgram quantities of highly stable, kinase-active ATM were prepared. Purified ATM was phosphorylated on serine 1981 and was active towards a variety of known ATM substrates, including p53 and the Bloom Syndrome helicase, BLM. The protein kinase activity of ATM was selectively inhibited by wortmannin, caffeine and LY294002 and was stimulated by charged biological polymers, including single-stranded M13 DNA (ssDNA), sheared double-stranded calf thymus DNA, heparin sulfate and poly ADP-ribose (PAR), raising the possibility that charged structures may contribute to regulation of ATM activity. However, chemical inhibition of the formation of poly ADP-ribose in cells had no effect on the activation of ATM-dependent pathways by ionizing radiation. Using gel filtration chromatography, we also show that purified ATM, as well as ATM in crude nuclear extracts from unirradiated and irradiated cells elutes with an estimated native molecular weight of approximately 600 kDa. Moreover, dephosphorylation of serine 1981 did not affect the apparent molecular weight of ATM in irradiated extracts. Our results suggest that phosphorylation of serine 1981 alone may not directly regulate the subunit composition of ATM. [Copyright &y& Elsevier]

Apoptosis is regulated by several pathways, such as caspases, mitogen activated protein kinase (MAPK) and cAMP/cAMP-dependent protein kinase A (PKA) cascade. This study investigated the effect of β2-adrenoceptor activation on Shiga toxin (Stx)2-induced apoptosis in renal tubular cells and the contribution of these signalling pathways. Cultured human adenocarcinoma-derived tubular cells were exposed to Stx2 (64 pg/mL) for 2–24 hr following the addition of the β2-adrenoceptor agonist (terbutaline) to the incubation medium. Stx2-induced apoptosis and its amelioration by β2-adrenoceptor activation was confirmed using DNA degradation assays and by flow cytometry for annexin V, mitochondrial membrane potential and caspase(-3 and -7) activity. Exposure of cells to Stx2 for 24 hr increased the DNA fragmentation to 11.6±0.9%, compared to 3.3±0.2% in control cells (P<0.05) but was decreased to approximately 5–7% (P<0.05) in the presence of terbutaline. Furthermore, Stx2-stimulated apoptosis, detected by TUNEL, annexin V and mitochondrial potential, was inhibited by terbutaline (P<0.05) which was prevented by cAMP-PKA inhibitors and a β2-adrenoceptor antagonist. However, inhibition of Stx2-mediated caspase activity by terbutaline was partially blocked by cAMP-PKA inhibitors. On the other hand, p38MAPK inhibition by terbutaline prevented Stx2-induced apoptosis and caspase activity through a cAMP-independent pathway via β2-adrenoceptor. These data indicate that β2-adrenoceptor activation can inhibit Stx2-induced apoptosis of the cells, which may be caused by a reduction in caspase activity through cAMP-PKA activation and the p38MAPK pathway. [Copyright &y& Elsevier]

NF-κB is a transcription factor known to promote or antagonize cell death depending on cell types and stimuli. Here, we demonstrate that expression of latent membrane protein 1 (LMP1), an Epstein–Barr virus (EBV)-encoded membrane protein, triggers programmed cell death in an NF-κB-dependent manner. Co-expression of NF-κB inhibitors completely prevented activation of NF-κB and LMP1-induced cell death. Addition therein of RelA, an active subunit of NF-κB, restored the NF-κB activation and cell death induction by LMP1, but RelA alone did not induce cell death. These results indicate that the activation of NF-κB is required for cell death induced by LMP1. Moreover, LMP1 induced activation of caspase-3 via the activation of NF-κB. Studies with z-VAD-fmk, a caspase inhibitor, indicated that NF-κB mediated both caspase-dependent and -independent death pathways. In conclusion, the cell death induced by LMP1 uncovered caspase-dependent and -independent death pathways both of which require NF-κB. [Copyright &y& Elsevier]

To examine the p53-mediated biological activities and signalling pathways, we generated stable transfectants of the p53-null IW32 murine erythroleukemia cells expressing the temperature-sensitive p53 mutant DNA, tsp53val135. Two clones with different levels of p53 protein expression were selected for further characterization. At permissive temperature, clone 1–5 cells differentiated along the erythroid pathway, and clone 3–2 cells that produced greater levels (3.5-fold) of p53 underwent apoptosis. Apoptosis of 3–2 cells was accompanied by mitochondrial cytochrome c release and caspase activation as well as by cleavage of caspase substrates. Bax protein was induced to a similar extent in these clones by wild-type p53; expression of p21Cip1/Waf1 and p27Kip1 proteins was also increased. However, significantly lesser extent of induction for both CDK inhibitors was detected in the apoptotic 3–2 clone. The general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) blocked the p53-induced apoptosis in 3–2 cells, with a concomitant elevation of p27Kip1, suggesting that p27Kip1 protein underwent caspase-dependent proteolysis in the apoptotic 3–2 cells. Together these results linked a pathway involving cytochrome c release, caspase activation and p27Kip1 degradation to the p53-induced apoptosis in IW32 erythroleukemia cells. [Copyright &y& Elsevier]

Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace. [ABSTRACT FROM AUTHOR]

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent anti-proliferative activity against those human cancer cell lines and compound 5r showed the most potent biological activity against HepG2 cells with an IC50 value of 10.56 ± 1.14 μΜ. In addition, bioassays showed that compound 5r induced time-dependent and dose-dependent cleavage of poly ADP-ribose polymerase (PARP), and also induced a dose-dependent increase in caspase-3 and caspase-8 activity, but had little effect on caspase-9 protease activity in HepG2 cells. These results provide evidence that 5r-induced apoptosis in HepG2 cell is caspase-8-dependent.