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DNA damage response (DDR) relies on swift and accurate signaling to rapidly identify DNA lesions and initiate repair. A critical DDR signaling and regulatory molecule is the posttranslational modification poly(ADP-ribose) (PAR). PAR is synthesized by a family of structurally and functionally diverse proteins called poly(ADP-ribose) polymerases (PARPs). Although PARPs share a conserved catalytic domain, unique regulatory domains of individual family members endow PARPs with unique properties and cellular functions. Family members PARP-1, PARP-2, and PARP-3 (DDR-PARPs) are catalytically activated in the presence of damaged DNA and act as damage sensors. Family members tankyrase-1 and closely related tankyrase-2 possess SAM and ankyrin repeat domains that regulate their diverse cellular functions. Recent studies have shown that the tankyrases share some overlapping functions with the DDR-PARPs, and even perform novel functions that help preserve genomic integrity. In this review, we briefly touch on DDR-PARP functions, and focus on the emerging roles of tankyrases in genome maintenance. Preservation of genomic integrity thus appears to be a common function of several PARP family members, depicting PAR as a multifaceted guardian of the genome.
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Daño del ADN , Reparación del ADN , Inestabilidad Genómica , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , Humanos , Modelos Moleculares , Poli(ADP-Ribosa) Polimerasas/química , Dominios Proteicos , Tanquirasas/química , Tanquirasas/metabolismoRESUMEN
We isolated a novel lectin (Artocarpus nitidus subsp. lingnanensis lectin, ALL) from Artocarpus nitidus subsp. lingnanensis and showed its mitogenic activities. In this study, we determined the amino acid sequence of ALL by cDNA sequencing. ALL cDNA (933 bp) contains a 657-bp open reading frame (ORF), which encodes a protein with 218 amino acids. ALL shares high sequence similarities with Jacalin and Morniga G and belongs to jacalin-related lectin family. We also examined the antitumor activity of ALL using Raji, a human B-lymphoma cell line. ALL exhibits a strong binding affinity to cell membrane, which can be effectively inhibited by N-acetyl-D-galactosamine (GalNAc). ALL inhibits Raji cell proliferation in a time- and dose-dependent manner through apoptosis, evidenced by morphological changes, phosphatidylserine externalization, poly ADP-ribose polymerase (PARP) cleavage, Bcl-2 down-regulation, and caspase-3 activation. We further showed that the activation of p38 mitogen-activated protein kinase (MAPK) signaling pathways is required for the pro-apoptotic activity of ALL.
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Apoptosis/genética , Artocarpus/genética , Linfoma de Células B/patología , Lectinas de Plantas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular Tumoral , Clonación Molecular , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Fosforilación/genética , Lectinas de Plantas/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.
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Ácidos Grasos Omega-3 , Neoplasias/dietoterapia , Antineoplásicos , Quimioradioterapia Adyuvante , Terapia Combinada , Dieta , Grasas de la Dieta , Humanos , Alimentos MarinosRESUMEN
Polyphenols have been described to have a wide range of biological activities, and many reports, published during recent years, have highlighted the beneficial effects of phenolic compounds, illustrating their promising role as therapeutic tools in several acute and chronic disorders. The purpose of study was to evaluate, in an already-assessed model of lung injury caused by bleomycin (BLM) administration, the role of resveratrol and quercetin, as well as to explore the potential beneficial properties of a mango leaf extract, rich in mangiferin, and a grape leaf extract, rich in dihydroquercetin (DHQ), on the same model. Mice were subjected to intra-tracheal administration of BLM, and polyphenols were administered by oral route immediately after BLM instillation and daily for 7 d. Treatment with resveratrol, mangiferin, quercetin and DHQ inhibited oedema formation and body weight loss, as well as ameliorated polymorphonuclear infiltration into the lung tissue and reduced the number of inflammatory cells in bronchoalveolar lavage fluid. Moreover, polyphenols suppressed inducible nitric oxide synthase expression, and prevented oxidative and nitroxidative lung injury, as shown by the reduced nitrotyrosine and poly (ADP-ribose) polymerase levels. The degree of apoptosis, as evaluated by Bid and Bcl-2 balance, was also suppressed after polyphenol treatment. Finally, these natural products down-regulated cyclo-oxygenase-2, extracellular signal-regulated kinase phosphorylated expression and reduced NF-κBp65 translocation. Our findings confirmed the anti-inflammatory effects of resveratrol and quercetin in BLM-induced lung damage, and highlight, for the first time, the protective properties of exogenous administration of mangiferin and DHQ on experimental pulmonary fibrosis.
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Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Suplementos Dietéticos , Modelos Animales de Enfermedad , Extractos Vegetales/uso terapéutico , Polifenoles/uso terapéutico , Fibrosis Pulmonar/prevención & control , Animales , Antiinflamatorios no Esteroideos/análisis , Antioxidantes/análisis , Apoptosis , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Mangifera/química , Ratones Endogámicos ICR , Infiltración Neutrófila , Extractos Vegetales/química , Hojas de la Planta/química , Polifenoles/análisis , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Quercetina/análogos & derivados , Quercetina/análisis , Quercetina/uso terapéutico , Distribución Aleatoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Resveratrol , Estilbenos/uso terapéutico , Vitis/química , Xantonas/análisis , Xantonas/uso terapéuticoRESUMEN
Overexpression of SIRT1 is frequently observed in various types of cancers, suggesting its potential role in malignancies. However, the molecular basis of how SIRT1 is elevated in cancer is less understood. Here we show that cancer-related SIRT1 overexpression is due to evasion of Sirt1 mRNA from repression by a group of Sirt1-targeting microRNAs (miRNAs) that might be robustly silenced in cancer. Our comprehensive library-based screening and subsequent miRNA gene profiling revealed a housekeeping gene-like broad expression pattern and strong CpG island-association of the Sirt1-targeting miRNA genes. This suggests aberrant CpG DNA methylation as the mechanistic background for malignant SIRT1 elevation. Our work also provides an example where epigenetic mechanisms cause the group-wide regulation of miRNAs sharing a common key target.
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Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Sirtuina 1/genética , Regiones no Traducidas 3'/genética , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Línea Celular Tumoral , Islas de CpG/genética , Metilación de ADN , Etopósido/farmacología , Células HeLa , Humanos , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2021.712556.].
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Introduction: T cell-dependent inflammatory response with the upregulation of helper 17 T cells (Th17) and the downregulation of regulatory T cells (Treg) accompanied by the increased production of tumor necrosis alpha (TNFa) is characteristic of inflammatory bowel diseases (IBD). Modulation of T cell response may alleviate the inflammation thus reduce intestinal damage. Poly(ADP-ribose) polymerase-2 (PARP2) plays role in the development, differentiation and reactivity of T cell subpopulations. Our aim was to investigate the potential beneficial effect of T cell-specific PARP2 downregulation in the lipopolysaccharide (LPS) induced inflammatory response of the cecum and the colon. Methods: Low-dose LPS was injected intraperitoneally to induce local inflammatory response, characterized by increased TNFa production, in control (CD4Cre; PARP2+/+) and T cell-specific conditional PARP2 knockout (CD4Cre; PARP2f/f) mice. TNFa, IL-1b, IL-17 levels were measured by ELISA, oxidative-nitrative stress was estimated by immunohistochemistry, while PARP1 activity, p38 MAPK and ERK phosphorylation, and NF-kB expression in large intestine tissue samples were examined by Western-blot. Systemic & local T cell subpopulation; Th17 and Treg alterations were also investigated using flowcytometry and immunohistochemistry. Results: In control animals, LPS induced intestinal inflammation with increased TNFa production, while no significant elevation of TNFa production was observed in T cell-specific PARP2 knockout animals. The absence of LPS-induced elevation in TNFa levels was accompanied by the absence of IL-1b elevation and the suppression of IL-17 production, showing markedly reduced inflammatory response. The increase in oxidative-nitrative stress and PARP1-activation was also absent in these tissues together with altered ERK and NF-kB activation. An increase in the number of the anti-inflammatory Treg cells in the intestinal mucosa was observed in these animals, together with the reduction of Treg count in the peripheral circulation. Discussion: Our results confirmed that T cell-specific PARP2 downregulation ameliorated LPS-induced colitis. The dampened TNFa production, decreased IL-17 production and the increased intestinal regulatory T cell number after LPS treatment may be also beneficial during inflammatory processes seen in IBD. By reducing oxidative-nitrative stress and PARP1 activation, T cell-specific PARP2 downregulation may also alleviate intestinal tissue damage.
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Enfermedades Inflamatorias del Intestino , Lipopolisacáridos , Animales , Ratones , Lipopolisacáridos/toxicidad , Interleucina-17/metabolismo , Regulación hacia Abajo , FN-kappa B/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Inflamación/inducido químicamente , Inflamación/patología , Enfermedades Inflamatorias del Intestino/patología , Colon/patología , Linfocitos T Reguladores/metabolismoRESUMEN
Introduction: Poly ADP-Ribose Polymerase-1 (PARP1), a DNA repair enzyme is implicated as a key molecule in the pathogenesis of several neurodegenerative disorders. Traumatic insults inducing oxidative stress results in its over-activation causing inflammation and cell death (Parthanatos). As PARP1 inhibition is known to reduce oxidative stress, we hypothesized that PARP1 inhibition by a known inhibitor 3-aminobenzamide (3AB) might recuperate the damage in an in vitro model of blast injury using HEI-OC1 cells (mouse auditory hair cells). Methods: Here, we evaluated the protective effect of 3AB on HEI-OC1 cells following single and repetitive blast overpressures (BOPs). Results: We found that inhibition of PARP1 b 3AB inhibits the PARP1 enzyme and its action of a post-translational modification i.e. formation of Poly ADP-Ribose Polymers which leads to massive ATP depletion. PARP inhibition (3AB treatment) reduced the oxidative stress (4HNE, a marker of lipid peroxidation, and 8OHdG, a marker of oxidative DNA damage) in cells exposed to single/repetitive BOPS through up-regulation of Nrf2, a transcriptional regulator of antioxidant defense and the GCLC, a rate limiting enzyme in the synthesis of glutathione. Discussion: Overall, we found that PARP inhibition by 3AB helps to maintain the viability of BOP-exposed auditory hair cells by recuperating the ATP pool from both mitochondrial and glycolytic sources.
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We report on the effects of ethanol (EtOH) and Poly (ADP-ribose) polymerase (PARP) inhibition on RNA ribosomal engagement, as a proxy for protein translation, in prefrontal cortical (PFC) pyramidal neurons. We hypothesized that EtOH induces a shift in RNA ribosomal-engagement (RE) in PFC pyramidal neurons, and that many of these changes can be reversed using a PARP inhibitor. We utilized the translating ribosome affinity purification (TRAP) technique to isolate cell type-specific RNA. Transgenic mice with EGFP-tagged Rpl10a ribosomal protein expressed only in CaMKIIα-expressing pyramidal cells were administered EtOH or normal saline (CTL) i.p. twice a day, for four consecutive days. On the fourth day, a sub-group of mice that received EtOH in the previous three days received a combination of EtOH and the PARP inhibitor ABT-888 (EtOH + ABT-888). PFC tissue was processed to isolate both, CaMKIIα pyramidal cell-type specific ribosomal-engaged RNA (TRAP-RNA), as well as genomically expressed total-RNA from whole tissue, which were submitted for RNA-seq. We observed EtOH effects on RE transcripts in pyramidal cells and furthermore treatment with a PARP inhibitor "reversed" these effects. The PARP inhibitor ABT-888 reversed 82% of the EtOH-induced changes in RE (TRAP-RNA), and similarly 83% in the total-RNA transcripts. We identified Insulin Receptor Signaling as highly enriched in the ethanol-regulated and PARP-reverted RE pool and validated five participating genes from this pathway. To our knowledge, this is the first description of the effects of EtOH on excitatory neuron RE transcripts from total-RNA and provides insights into PARP-mediated regulation of EtOH effects.
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PARP inhibitors have clinically demonstrated good antitumor activity in patients with BRCA mutations. Here, we described YHP-836, a novel PARP inhibitor, YHP-836 demonstrated excellent inhibitory activity for both PARP1 and PARP2 enzymes. It also allosterically regulated PARP1 and PARP2 via DNA trapping. YHP-836 showed cytotoxicity in tumor cell lines with BRCA mutations and induced cell cycle arrest in the G2/M phase. YHP-836 also sensitized tumor cells to chemotherapy agents in vitro. Oral administration of YHP-836 elicited remarkable antitumor activity either as a single agent or in combination with chemotherapy agents in vivo. These results indicated that YHP-836 is a well-defined PARP inhibitor.
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DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.
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Synthetic lethality (SL) is an emerging therapeutic paradigm in cancer. We introduced a different approach to prioritize SL gene pairs through literature mining and RAS-mutant high-throughput screening (HTS) data. We matched essential genes from text-mining and mutant genes from the COSMIC and CCLE HTS datasets to build a prediction model of SL gene pairs. CCLE gene expression data were used to enrich the essential-mutant SL gene pairs using Spearman's correlation coefficient and literature mining. In total, 223 essential trigger terms were extracted and ranked. The threshold of the essential gene score ( S g ) was set to 10. We identified 586 genes essential for the SL prediction model of colon cancer. Seven essential RAS-mutant SL gene pairs were identified in our model, including CD82-KRAS/NRAS, PEBP1-NRAS, MT-CO2-HRAS, IFI27-NRAS/KRAS, and SUMO1-HRAS gene pairs. Using RAS-mutant HTS data validation, we identified two potential SL gene pairs, including the CD82 (essential gene)-KRAS (mutant gene) pair and CD82-NRAS pair in the DLD-1 colon cancer cell line (Spearman's correlation p-values = 0.004786 and 0.00249, respectively). Based on further annotations by PubChem, we observed that digitonin targeted the complex comprising CD82, especially in KRAS-mutated HCT116 cancer cells. Moreover, we experimentally demonstrated that CD82 exhibited selective vulnerability in KRAS-mutant colorectal cancer. We used literature mining and HTS data to identify candidates for SL targets for RAS-mutant colon cancer.
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Introduction: The development of cancer generally occurs as a result of various deregulated molecular mechanisms affecting the genes that can control normal cellular growth. Signal transducer and activator of transcription 3 (STAT3) pathway, once aberrantly activated can promote carcinogenesis by regulating the transcription of a number of oncogenic genes. Objectives: Here, we evaluated the impact of fangchinoline (FCN) to attenuate tumor growth and survival through modulation of oncogenic STAT3 signaling pathway using diverse tumor cell lines and a xenograft mouse model. Methods: To evaluate the action of FCN on STAT3 cascade, protein levels were analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA). Translocation of STAT3 was detected by immunocytochemistry. Thereafter, FCN-induced ROS was measured by GSH/GSSG assay and H2DCF-DA. FCN-induced apoptosis was analyzed using Western blot analysis and flow cytometry for various assays. Finally, anti-cancer effects of FCN in vivo was evaluated in a myeloma model. Results: We noted that FCN abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src). In addition, FCN also attenuated DNA binding ability of STAT3 and its translocation into the nucleus. It altered the levels of upstream signaling proteins, increased SHP-1 levels, and induced substantial apoptosis in U266 cells. FCN also promoted an increased production of reactive oxygen species (ROS) and altered GSSG/GSH ratio in tumor cells. Moreover, FCN effectively abrogated tumor progression and STAT3 activation in a preclinical myeloma model. Conclusion: Overall, this study suggests that FCN may have a tremendous potential to alter abnormal STAT3 activation and induce cell death in malignant cells along with causing the suppression of pathogenesis and growth of cancer through a pro-oxidant dependent molecular mechanism.
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Mieloma Múltiple , Factor de Transcripción STAT3 , Animales , Bencilisoquinolinas , Ratones , Mieloma Múltiple/tratamiento farmacológico , Estrés Oxidativo , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Factor de Transcripción STAT3/metabolismoRESUMEN
Introduction: Phosphoinositide 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of various diseases, and the diverse physiological roles of class I PI3K isoforms (α, ß, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. However, the high structural conservation among the PI3K family makes it a big challenge to develop selective PI3Kγ inhibitors. Objectives: A novel machine learning-based virtual screening with multiple PI3Kγ protein structures was developed to discover novel PI3Kγ inhibitors. Methods: A large chemical database was screened using the virtual screening model, the top-ranked compounds were then subjected to a series of bio-evaluations, which led to the discovery of JN-KI3. The selective inhibition mechanism of JN-KI3 against PI3Kγ was uncovered by a theoretical study. Results: 49 hits were identified through virtual screening, and the cell-free enzymatic studies found that JN-KI3 selectively inhibited PI3Kγ at a concentration as low as 3,873 nM but had no inhibitory effect on Class IA PI3Ks, leading to the selective cytotoxicity on hematologic cancer cells. Meanwhile, JN-KI3 potently blocked the PI3K signaling, finally led to distinct apoptosis of hematologic cell lines at a low concentration. Lastly, the key residues of PI3Kγ and the structural characteristics of JN-KI3, which both would influence γ isoform-selective inhibition, were highlighted by systematic theoretical studies. Conclusion: The developed virtual screening model strongly manifests the robustness to find novel PI3Kγ inhibitors. JN-KI3 displays a specific cytotoxicity on hematologic tumor cells, and significantly promotes apoptosis associated with the inhibition of the PI3K signaling, which depicts PI3Kγ as a potential target for the hematologic tumor therapy. The theoretical results reveal that those key residues interacting with JN-KI3 are less common compared to most of the reported PI3Kγ inhibitors, indicating that JN-KI3 has novel structural characteristics as a selective PIK3γ inhibitor.
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Simulación de Dinámica Molecular , Fosfatidilinositol 3-Quinasas , Aprendizaje Automático , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3RESUMEN
Triple-negative breast cancer is a combative cancer type with a highly inflated histological grade that leads to poor theragnostic value. Gene, protein, and receptor-specific targets have shown effective clinical outcomes in patients with TNBC. Cells are frequently exposed to DNA-damaging agents. DNA damage is repaired by multiple pathways; accumulations of mutations occur due to damage to one or more pathways and lead to alterations in normal cellular mechanisms, which lead to development of tumors. Advances in target-specific cancer therapies have shown significant momentum; most treatment options cause off-target toxicity and side effects on healthy tissues. PARP (poly(ADP-ribose) polymerase) is a major protein and is involved in DNA repair pathways, base excision repair (BER) mechanisms, homologous recombination (HR), and nonhomologous end-joining (NEJ) deficiency-based repair mechanisms. DNA damage repair deficits cause an increased risk of tumor formation. Inhibitors of PARP favorably kill cancer cells in BRCA-mutations. For a few years, PARPi has shown promising activity as a chemotherapeutic agent in BRCA1- or BRCA2-associated breast cancers, and in combination with chemotherapy in triple-negative breast cancer. This review covers the current results of clinical trials testing and future directions for the field of PARP inhibitor development.
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Introduction: Approximately 300,000 women worldwide are diagnosed each year with ovarian cancer. Frequently diagnosed in late stages with ambiguous symptomatology, ovarian cancer has a low survival rate.Areas covered: Niraparib, a PARP inhibitor, was approved in 2020 for use in the maintenance treatment of ovarian cancer regardless of biomarker status. Included in the review are PRIMA (NCT02655016), NOVA (NCT01847274), AVANOVA2 (NCT02354131), and QUADRA (NCT02354586) trials which herald the advent of using maintenance oral therapies in the treatment of ovarian cancer. Additionally, with new combination drug trials, exciting avenues for treatment are also discussed with the FIRST (NCT03016338) trial.Expert opinion: Maintenance niraparib treatment regardless of genetic profile offers a new modality for the treatment of ovarian cancer with a low side effect profile and importantly oral dosing. New combinations of synergistic immunotherapeutics, and antiangiogenesis therapies with niraparib also offer exciting new frontiers for patients with ovarian cancer.
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Trompas Uterinas , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Femenino , Humanos , Indazoles , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , PiperidinasRESUMEN
Preserving genome integrity through repair of DNA damage is critical for human health and defects in these pathways lead to a variety of pathologies, most notably cancer. The social amoeba Dictyostelium discoideum is remarkably resistant to DNA damaging agents and genome analysis reveals it contains orthologs of several DNA repair pathway components otherwise limited to vertebrates. These include the Fanconi Anemia DNA inter-strand crosslink and DNA strand break repair pathways. Loss of function of these not only results in malignancy, but also neurodegeneration, immune-deficiencies and congenital abnormalities. Additionally, D. discoideum displays remarkable conservations of DNA repair factors that are targets in cancer and other therapies, including poly(ADP-ribose) polymerases that are targeted to treat breast and ovarian cancers. This, taken together with the genetic tractability of D. discoideum, make it an attractive model to assess the mechanistic basis of DNA repair to provide novel insights into how these pathways can be targeted to treat a variety of pathologies. Here we describe progress in understanding the mechanisms of DNA repair in D. discoideum, and how these impact on genome stability with implications for understanding development of malignancy.
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AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.
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Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/enzimología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Animales , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/metabolismo , Humanos , Terapia Molecular Dirigida , Enfermedades Neurodegenerativas/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed a2, a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that a2 induced ferroptosis. Importantly, compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2. Furthermore, we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition. Moreover, a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2, and GPX4 downregulation indicated the sensitivity of tumors to a2. Finally, a2 exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2, and a2 will hopefully serve as a promising compound for gastric cancer treatment.
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Consistent STAT3 (Single transducer and activator of transcription 3) activation is observed in many tumors and promotes malignant cell transformation. In the present investigation, we evaluated the anticancer effects of Parrotiopsis jacquemontiana methanol fraction (PJM) on STAT3 inhibition in HCCLM3 and MDA-MB 231 cells. PJM suppressed the activation of upstream kinases i.e. JAK-1/2 (Janus kinase-1/2), and c-Src (Proto-oncogene tyrosine-protein kinase c-Src), and upregulated the expression levels of PIAS-1/3 (Protein Inhibitor of Activated STATs-1/3), SHP-1/2 (Src-homology region 2 domain-containing phosphatase-1/2), and PTP-1ß (Protein tyrosine phosphatase 1 ß) which negatively regulate STAT3 signaling pathway. PJM also decreased the levels of protein products conferring to various oncogenes, which in turn repressed the proliferation, migration, invasion, and induced apoptosis in cancer cell lines. The growth inhibitory effects of PJM on cell-cycle and metastasis were correlated with decreased expression levels of CyclinD1, CyclinE, MMP-2 (Matrix metalloproteinases-2), and MMP-9 (Matrix metalloproteinases-9). Induction of apoptosis was indicated by the cleavage and subsequent activation of Caspases (Cysteine-dependent Aspartate-directed Proteases) i.e. caspase-3, 7, 8, 9, and PARP (Poly (ADP-ribose) polymerase) as well as through the down-regulation of anti-apoptotic proteins. These apoptotic effects of PJM were preceded by inhibition of STAT3 cell-signaling pathway. STAT3 was needed for PJM-induced apoptosis, and inhibition of STAT3 via pharmacological inhibitor (Stattic; SC-203282) abolished the apoptotic effects. Conclusively, our results demonstrate the capability of PJM to inhibit cancer cell-proliferation and induce apoptosis by suppressing STAT3 via upregulation of STAT3 inhibitors and pro-apoptotic proteins whereas the down-regulation of upstream kinases and anti-apoptotic protein expression. In future, one-step advance studies of PHM regarding its role in metastatic inhibition, immune response modulation for reducing tumor, and inducing apoptosis in suitable animal models would be an interesting and promising research area.