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1.
Mitochondrion ; 67: 59-64, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36367519

RESUMO

The low cerebral metabolic rate of oxygen despite the relatively preserved perfusion in Alzheimer's disease (AD) patients' medial temporal lobes suggest histotoxic hypoxia due to mitochondrial dysfunction that is independent of, but could precede, insulin resistance. Neuropathological, metabolomic, and preclinical evidence are consistent with the notion that this mitochondrial dysfunction may be contributed to by oxidative stress and DNA damage, leading to poly-(ADP-ribose)-polymerase-1 (PARP1) activation and consequent AMP accumulation, clogging of mitochondrial adenine nucleotide transporters (ANTs), matrix ADP deprivation, and ATP synthase inhibition. Complementary mechanisms may include mitochondrial-protein poly-ADP-ribosylation and mitochondrial-biogenesis suppression via PARPs outcompeting Sirtuin-1 (SIRT1) for nicotinamide-adenine-dinucleotide (NAD+).


Assuntos
Doença de Alzheimer , Poli(ADP-Ribose) Polimerases , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Estresse Oxidativo , NAD/metabolismo , Dano ao DNA , Hipóxia , Trifosfato de Adenosina/metabolismo , Monofosfato de Adenosina , Difosfato de Adenosina/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo
2.
J Transl Med ; 20(1): 521, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348405

RESUMO

BACKGROUND: We reported that PARP-1 regulates genes whose products are crucial for asthma, in part, by controlling STAT6 integrity speculatively through a calpain-dependent mechanism. We wished to decipher the PARP-1/STAT6 relationship in the context of intracellular trafficking and promoter occupancy of the transcription factor on target genes, its integrity in the presence of calpains, and its connection to autophagy. METHODS: This study was conducted using primary splenocytes or fibroblasts derived from wild-type or PARP-1-/- mice and Jurkat T cells to mimic Th2 inflammation. RESULTS: We show that the role for PARP-1 in expression of IL-4-induced genes (e.g. gata-3) in splenocytes did not involve effects on STAT6 phosphorylation or its subcellular trafficking, rather, it influenced its occupancy of gata-3 proximal and distal promoters in the early stages of IL-4 stimulation. At later stages, PARP-1 was crucial for STAT6 integrity as its inhibition, pharmacologically or by gene knockout, compromised the fate of the transcription factor. Calpain-1 appeared to preferentially degrade JAK-phosphorylated-STAT6, which was blocked by calpastatin-mediated inhibition or by genetic knockout in mouse fibroblasts. The STAT6/PARP-1 relationship entailed physical interaction and modification by poly(ADP-ribosyl)ation independently of double-strand-DNA breaks. Poly(ADP-ribosyl)ation protected phosphorylated-STAT6 against calpain-1-mediated degradation. Additionally, our results show that STAT6 is a bonafide substrate for chaperone-mediated autophagy in a selective and calpain-dependent manner in the human Jurkat cell-line. The effects were partially blocked by IL-4 treatment and PARP-1 inhibition. CONCLUSIONS: The results demonstrate that poly(ADP-ribosyl)ation plays a critical role in protecting activated STAT6 during Th2 inflammation, which may be synthetically targeted for degradation by inhibiting PARP-1.


Assuntos
Poli ADP Ribosilação , Poli(ADP-Ribose) Polimerases , Humanos , Camundongos , Animais , Poli(ADP-Ribose) Polimerases/metabolismo , Calpaína/genética , Calpaína/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Autofagia , Inflamação , Fator de Transcrição STAT6/metabolismo
3.
DNA Repair (Amst) ; 120: 103423, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36356486

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are DNA-dependent poly(ADP-ribose)transferases localized in nucleus. They have a significant homology in the C-terminal catalytic domain structure but differ in their N-terminal DNA-binding parts. The structural difference has an impact on the interaction of PARP1 and PARP2 with DNA and their DNA-dependent activation. Here, we compare the interaction of PARP1 and PARP2 with free 147 bp nucleosomal DNA and its nucleosome-associated variant (NCP) that contain in one strand a 1-nucleotide gap with 5'-dRP (imitating the intermediate of Base Excision Repair) or no specific damage. The affinity of PARP2 for the DNA strongly depends on the gap presence and to a lesser extent on the association with nucleosomes, while PARP1 interacts primarily with blunt ends of all DNAs and with a lower affinity with the single-strand break. The activities of PARP1 and PARP2 in the autoPARylation reaction and heteromodification of histones are distinctly stimulated by HPF1, depending on the gap presence in activating DNA. The most significant HPF1-induced stimulation of the histone modification in the presence of gapped NCP is a peculiar feature of PARP2. We propose a specific regulatory role of PARP2 in the process of DNA repair in the context of chromatin.


Assuntos
Histonas , Poli ADP Ribosilação , Histonas/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Reparo do DNA , Poli(ADP-Ribose) Polimerase-1/metabolismo , DNA/metabolismo , Nucleossomos , Catálise
4.
J Virol ; 96(21): e0037122, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36286483

RESUMO

Gammaherpesviruses, including Epstein-Barr virus (EBV), are important human pathogens because they are associated with various tumors. Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional host nuclear protein responsible for poly(ADP-ribosyl)ation (PARylation) of target proteins. While PARP1 acts as a negative regulator that suppresses the lytic replication of gammaherpesviruses, viruses are often equipped with various strategies to overcome PARP1 inhibition. However, the mechanisms of how EBV may modulate a repressive host protein, PARP1, are still elusive. In this study, we found that EBV reactivation induced PARP1 downregulation in EBV-infected cells. EBV DNA polymerase processivity factor EA-D, encoded by the BMRF1 gene, directly interacted with the central automodification domain (AD) of PARP1 and was necessary and sufficient to downregulate PARP1 via K29-linked polyubiquitination. Moreover, knockdown of EA-D in B95.8 cells restored PARP1 levels and abrogated the expression of ZTA (also known as ZEBRA), a switch molecule of the EBV life cycle during reactivation. Interestingly, PARP1 PARylated RTA, another key switch molecule, and decreased RTA transactivation on the promoters of the ZTA, BMRF1, and BMLF1 genes. EA-D alleviated the PARylation of RTA and further enhanced RTA-mediated transactivation of these lytic promoters in reporter assays. Taken together, our results suggest that EBV viral processivity factor plays a key role in facilitating lytic replication by inducing PARP1 degradation via its interaction with the PARP1 AD, which is a highly conserved mechanism among gammaherpesviruses to counteract host repressive activity of PARP1 against viral lytic replication. IMPORTANCE PARP1 acts as a negative regulator of lytic replication in EBV. To successfully enter the reactivation cycle, EBV has developed multiple strategies to counteract the host's repressive mechanisms. In this study, we investigated how EBV manipulated the host repressive factor PARP1 to facilitate lytic replication. The EBV processivity factor EA-D downregulated PARP1 in a proteasome-dependent manner via its direct binding with PARP1 AD. The knockdown of EA-D restored the PARP1 level and inhibited ZTA expression during reactivation. Interestingly, PARP1 PARylated RTA and EA-D reduced the PARylation of RTA, thereby promoting the ZTA promoter activity. These results suggest that EA-D plays a key role in EBV lytic replication by inducing PARP1 degradation in addition to supporting DNA replication as a viral processivity factor. Given that the KSHV processivity factor also induces PARP1 degradation and enhances RTA function, gammaherpesviruses share a conserved molecular mechanism to overcome the inhibitory effects of PARP1, promoting lytic replication.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Fator D do Complemento/genética , Infecções por Vírus Epstein-Barr/genética , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/genética , Regiões Promotoras Genéticas , Replicação Viral/genética , Poli(ADP-Ribose) Polimerases/metabolismo
5.
J Mol Model ; 28(11): 340, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36194315

RESUMO

Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.


Assuntos
Antineoplásicos , Produtos Biológicos , Neoplasias , Difosfato de Adenosina , Alcaloides , Antineoplásicos/química , Antineoplásicos/farmacologia , Caspases , Feminino , Humanos , Isoquinolinas , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose
6.
Neurochem Int ; 161: 105435, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36273706

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is an omnipresent metabolite that participates in redox reactions. Multiple NAD+-consuming enzymes are implicated in numerous biological processes, including transcription, signaling, and cell survival. Multiple pieces of evidence have demonstrated that NAD+-consuming enzymes, including poly(ADP-ribose) polymerases (PARPs), sirtuins (SIRTs), and sterile alpha and TIR motif-containing 1 (SARM1), play major roles in peripheral neuropathic pain of various etiologies. These NAD+ consumers primarily participate in peripheral neuropathic pain via mechanisms such as mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, NAD+ synthase and nicotinamide phosphoribosyltransferase (NAMPT) have recently been found to contribute to the regulation of pain. Here, we review the evidence indicating the involvement of NAD+ metabolism in the pathological mechanisms of peripheral neuropathic pain. Advanced understanding of the molecular and cellular mechanisms associated with NAD+ in peripheral neuropathic pain will facilitate the development of novel treatment options for diverse types of peripheral neuropathic pain.


Assuntos
Neuralgia , Sirtuínas , Humanos , NAD/metabolismo , Sirtuínas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Oxirredução
7.
Nat Cancer ; 3(10): 1211-1227, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36253486

RESUMO

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK-p-Tyr19-CDK9 expression.


Assuntos
Quinase do Linfoma Anaplásico , Antineoplásicos , Neoplasias da Mama , Quinase 9 Dependente de Ciclina , Animais , Feminino , Humanos , Camundongos , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/farmacologia , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Quinase 9 Dependente de Ciclina/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Fator B de Elongação Transcricional Positiva , Tirosina/química , Tirosina/metabolismo , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Estados Unidos
8.
Eur J Med Chem ; 243: 114790, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36183505

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 µM and 8.93 µM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.


Assuntos
Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/química , Simulação de Acoplamento Molecular , Caspase 3/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ureia/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/química , Proliferação de Células , Poli(ADP-Ribose) Polimerase-1 , Relação Estrutura-Atividade , Benzamidas/farmacologia
9.
Oncol Rep ; 48(6)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36263616

RESUMO

The primary subtypes of renal cell carcinoma (RCC) include clear cell, papillary and chromophobe RCC. RCC occurs often due to loss of von Hippel­Lindau (VHL) and accumulation of lipids and glycogen, and RCC cells may exhibit sensitivity to the disruption of normal metabolism or homologous recombination gene defect. Although the application of molecular­targeted drugs (tyrosine kinase inhibitors) and immune checkpoint inhibitors has been recommended for the treatment of advanced RCC, more targets of DNA damage repair (DDR) signaling pathway involved in the synthetic lethal effect have been investigated. However, although achievements has been made in the exploration of the roles of DDR genes on RCC progression, their association has not been systematically summarized. Poly (ADP­ribose) polymerase (PARP) 1 inhibitors are used in tumors with BRCA1/2 DNA repair­associated mutations. PARP family enzymes perform post­translational modification functions and participate in DDR and cell death. Inhibitors of PARP, ataxia telangiectasia mutant gene and polymerase θ serve key roles in the treatment of specific RCC subtypes. PARP1 may serve as an important biological marker to predict the therapeutic effect of immune checkpoint inhibitors and evaluate the prognosis of patients with ccRCC with polybromo 1 mutation. Therefore, the roles of DDR pathway on RCC progression or treatment may hold promises for the treatment of certain specific types of RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Checkpoint Imunológico , Ribose , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Reparo do DNA , Poli(ADP-Ribose) Polimerases/metabolismo , Dano ao DNA , Inibidores de Proteínas Quinases , Glicogênio , Lipídeos , Difosfato de Adenosina
10.
Bioorg Med Chem Lett ; 76: 129020, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36216031

RESUMO

In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4-d]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC50 = 0.59 µM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers.


Assuntos
Antineoplásicos , Apoptose , Pirimidinas , Humanos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
11.
Oncotarget ; 13: 1078-1091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187556

RESUMO

PARP10 is a mono-ADP-ribosyltransferase with multiple cellular functions, including proliferation, apoptosis, metabolism and DNA repair. PARP10 is overexpressed in a significant proportion of tumors, particularly breast and ovarian cancers. Identifying genetic susceptibilities based on PARP10 expression levels is thus potentially relevant for finding new targets for precision oncology. Here, we performed a series of CRISPR genome-wide loss-of-function screens in isogenic control and PARP10-overexpressing or PARP10-knockout cell lines, to identify genetic determinants of PARP10-mediated cellular survival. We found that PARP10-overexpressing cells rely on multiple DNA repair genes for survival, including ATM, the master regulator of the DNA damage checkpoint. Moreover, we show that PARP10 impacts the recruitment of ATM to nascent DNA upon replication stress. Finally, we identify the CDK2-Cyclin E1 complex as essential for proliferation of PARP10-knockout cells. Our work identifies a network of functionally relevant PARP10 synthetic interactions, and reveals a set of factors which can potentially be targeted in personalized cancer therapy.


Assuntos
Neoplasias , Poli(ADP-Ribose) Polimerases , ADP Ribose Transferases/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , DNA , Humanos , Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Medicina de Precisão , Proteínas Proto-Oncogênicas/genética
12.
Sci Rep ; 12(1): 15534, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109561

RESUMO

In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblastoma, the most aggressive type of brain cancer. The absence of PARP3 did not alter cell proliferation nor the in vivo tumorigenic potential of glioblastoma cells. We identified a physical and functional interaction of PARP3 with the histone H3 lysine 9 methyltransferase G9a. We show that PARP3 helps to adjust G9a-dependent repression of the adhesion genes Nfasc and Parvb and the hypoxia-responsive genes Hif-2α, Runx3, Mlh1, Ndrg1, Ndrg2 and Ndrg4. Specifically for Nfasc, Parvb and Ndrg4, PARP3/G9a cooperate for an adjusted establishment of the repressive mark H3K9me2. While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.


Assuntos
Neoplasias Encefálicas , Complemento C9/metabolismo , Glioblastoma , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/metabolismo , Glioblastoma/genética , Histonas , Humanos , Hipóxia , Lisina , Metiltransferases/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo
13.
DNA Cell Biol ; 41(10): 861-870, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36067068

RESUMO

Varicoceles (VCs) have received widespread attention as a primary factor affecting male fertility and a pathological condition that may lead to decreased sperm count and motility in patients. Many studies have shown that an imbalance of local antioxidant balance exists in patients with VC, leading to an obvious increase in the content of reactive oxygen species (ROS) and may cause reductive stress. Excessive ROS may aggravate spermatogenesis dysfunction and affect male fertility. Poly(ADP-ribose) polymerase (PARP) is an enzyme associated with DNA repair in eukaryotic cells, can be activated by DNA fragments with structural damage, and has been considered a DNA damage receptor in DNA damage repair and apoptosis. We built a rat model of VC and an oxidative damage model of a spermatocyte-derived cell line (GC-2 cells) induced by hydrogen peroxide to study the role of PARP1 in VC. Differentially expressed genes (DEGs) were obtained by RNA sequencing in the testes of VC rats. Analysis of DEGs revealed some genes with significantly altered expression, which were validated in rat and cell models. Immunofluorescence, real-time quantitative PCR analysis, Western blot, and flow cytometry were used to analyze the changes between the control group and the VC or hydrogen peroxide group. Overall, we found that PARP1 protein expression increased in VC rats and in the hydrogen peroxide-induced oxidative stress model of GC-2 cells. Parthanatos may be one of the factors leading to reduced reproductive capacity in VC patients. Our study provides novel insights into the mechanisms of male infertility induced by oxidative stress and provides a new therapeutic target for VC.


Assuntos
Parthanatos , Varicocele , Humanos , Masculino , Ratos , Animais , Varicocele/genética , Varicocele/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Peróxido de Hidrogênio/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Sêmen/metabolismo , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/farmacologia
14.
PLoS One ; 17(9): e0272916, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36103462

RESUMO

We recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting pathways of the host. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wild type (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 µM, 8.5 µM, 24.1 µM, 8.2 µM and 13.6 µM, respectively. A separate experiment focusing on a combination of 10 µM stenoparib and 0.5 µM remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.


Assuntos
COVID-19 , Poli(ADP-Ribose) Polimerases , Difosfato de Adenosina , COVID-19/tratamento farmacológico , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose , SARS-CoV-2
15.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077221

RESUMO

Poly ADP-ribosylation (PARylation) is a post-translational modification process. Following the discovery of PARP-1, numerous studies have demonstrated the role of PARylation in the DNA damage and repair responses for cellular stress and DNA damage. Originally, studies on PARylation were confined to PARP-1 activation in the DNA repair pathway. However, the interplay between PARylation and DNA repair suggests that PARylation is important for the efficiency and accuracy of DNA repair. PARylation has contradicting roles; however, recent evidence implicates its importance in inflammation, metabolism, and cell death. These differences might be dependent on specific cellular conditions or experimental models used, and suggest that PARylation may play two opposing roles in cellular homeostasis. Understanding the role of PARylation in cellular function is not only important for identifying novel therapeutic approaches; it is also essential for gaining insight into the mechanisms of unexplored diseases. In this review, we discuss recent reports on the role of PARylation in mediating diverse cellular functions and homeostasis, such as DNA repair, inflammation, metabolism, and cell death.


Assuntos
Poli ADP Ribosilação , Poli(ADP-Ribose) Polimerases , Reparo do DNA , Humanos , Inflamação , Poli ADP Ribosilação/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo
16.
Cells ; 11(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36078035

RESUMO

NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation-reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.


Assuntos
Neoplasias , Sirtuínas , Adenosina Difosfato Ribose , Humanos , NAD/metabolismo , Neoplasias/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Sirtuínas/metabolismo
17.
Biomed Pharmacother ; 153: 113458, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076571

RESUMO

Since the concept, DNA damage repair has been stated as a natural biological event, and research has increasingly revealed its strong association to tumors, aging, immunity, biochemical detection, and other factors. The discovery of abnormal DNA repair in cancers has been heralded as a paradigm shift in the treatment of malignancies. A poly (ADP-ribose) polymerase (PARP) activates poly (ADP-ribosylation) to repair single-strand DNA breaks after DNA damage. In some cancers, such as breast cancer and gastric cancer, a PARP inhibitor can target the DNA damage response pathway, prevent DNA repair, and induce homologous recombination deficiency (HRD) tumors to create the phenomena of synthetic lethality. Increasingly, clinical trials are being submitted to research the uses of PARP inhibitors in various types of cancers. Small cell lung cancer (SCLC) is a quickly growing malignancy with numerous therapeutic limitations and a dismal prognosis. Sequencing of mutant genes revealed multiple gene connections that may contribute to its carcinogenesis, indicating a viable study direction. Furthermore, the therapy of SCLC with PARP inhibitors has been further explored. The mechanism of PARP action, as well as the advancement of its preclinical and clinical applications in SCLC, will be discussed in this review.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Reparo do DNA , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
18.
Biomed Pharmacother ; 153: 113504, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076593

RESUMO

Post-translational modification of nuclear proteins through the addition of poly(ADP-ribose) (pADPr) moieties is upregulated in many metastatic cancers, where the high levels of pADPr have often been associated with poor cancer prognosis. Although the inhibitors of poly(ADP-ribose) polymerases (PARPs) have been utilized as potent anti-cancer agents, their efficacy in clinical trials varied among patient groups and has often been unpredictable. Such outcome cannot be interpreted solely by the inability to keep PARP-driven DNA repair in check. The focus of studies on PARP-driven tumorigenesis have recently been shifted toward PARP-dependent regulation of transcription. Here we utilized the controlled overexpression of poly(ADP-ribose) glycohydrolase (PARG), a sole pADPr-degrading enzyme, to investigate pADPr-dependent gene regulation in prostate cancer PC-3 cells. We demonstrated that PARG upregulation reduces pADPr levels and inhibits the expression of genes in key tumor-promoted pathways, including TNFα/NF-kB, IL6/STAT3, MYC, and KRAS signaling, the genes involved in inflammation response, especially chemokines, and endothelial-mesenchymal transition. The observed effect of PARG on transcription was consistent across all tested prostate cancer cell lines and correlates with PARG-induced reduction of clonogenic potential of PC-3 cells in vitro and a significant growth inhibition of PC-3-derived tumors in nude mice in vivo.


Assuntos
Glicosídeo Hidrolases , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata , Animais , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Regulação para Cima/genética
19.
Med Oncol ; 39(12): 241, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36180646

RESUMO

When DNA repair is inadequate it increases the chances of the genome becoming unstable and it undergoes a malignant mutation. The deficiency of DNA repair PARP proteins may be leveraged for cancer therapy by increasing genomic instability and causing massive DNA damage in cancer cells. DNA repair components are under increased demand in cancer cells because of the continuous replication of DNA. The oncogenic loss of BRCA and an inefficient DNA repair led to cancer cells being dependent on particular DNA repair pathways, like the Poly (ADP-ribose) polymerase pathway. Breast cancer gene 1 and 2 plays a crucial role in DNA repair and genome integrity explaining how BRCA1 and BRCA2 mutations raise the menace of cancer. PARP inhibitors inhibit the base exclusion repair pathway, resulting in the buildup of unrepaired single strand breaks, which cause inflated replication forks in the S phase and subsequently the development of damaging double stranded breaks. Cells having BRCA mutations are unable to repair DNA breaks, leading to apoptosis and eventually death of cancer cells. Numerous indicators, such as a lack of homologous recombination and a high degree of replication pressure, indicate that this therapy will be very effective. Combining PARP inhibitors with chemotherapy, an immune checkpoint inhibitor, and a targeted drug is an effective strategy for combating PARP inhibitors resistance. Several PARP-based combination approaches are in preclinical and clinical development. Various clinical trials are successfully completed and some are undergoing to evaluate the efficacy of these molecules. This review will describe the current views and clinical updates on PARP inhibitors.


Assuntos
Neoplasias , Inibidores de Poli(ADP-Ribose) Polimerases , Difosfato de Adenosina , DNA , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose
20.
Chemistry ; 28(63): e202202405, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-35952312

RESUMO

Herein we have reported the discovery of a pentacyclic building block comprised of fused indole-quinoline and piperidinone from the natural product perophoramidine as a formidable anticancer agent. The compounds were synthesized in six steps where the key steps involved a blue LED mediated intramolecular cyclopropanation of the indole intermediates and concomitant reduction of the associated aryl nitro moiety to nitroso in the molecule. Cytotoxicity screening of the compounds against an array of cancer cells that is, MCF7, HCT116 and A549 demonstrated 0.6 to 9 µM IC50 s by few of the compounds. γH2AX immunofluorescence assay of the two most potent molecules from the phenotypic screening with anti-γ-H2AX Alexa Fluor 488 antibody revealed extensive DNA damage of the A549 cells which indicated probable PARP inhibition (similar to Perophoramidine). Through molecular docking and molecular dynamic (MD) simulation studies the binding efficiency of our compounds with poly(ADP-ribose)polymerase 1 (PARP 1) enzyme was determined. Chemiluminescent PARP Assay with Histone-coated strips indicated that the most active compounds from the phenotypic screening induced PARP-1 inhibition with IC50 s of 1.3→1.5 µM.


Assuntos
Quebras de DNA de Cadeia Dupla , Inibidores de Poli(ADP-Ribose) Polimerases , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Simulação de Acoplamento Molecular , Poli(ADP-Ribose) Polimerase-1 , DNA , Indóis
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