Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.302
Filtrar
1.
Nat Commun ; 13(1): 2400, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504881

RESUMO

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.


Assuntos
Neoplasias Encefálicas , Neoplasias da Próstata , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Humanos , Masculino , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Reparo de DNA por Recombinação/genética
2.
Investig Clin Urol ; 63(3): 350-358, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35534220

RESUMO

PURPOSE: Our purpose was to verify the effects of atorvastatin (ATO) on prostate cancer (PCa) proliferation, apoptosis, invasion, and metastasis and to further explore the drug's mechanism of action. MATERIALS AND METHODS: We used cell counting kit-8 (CCK8) and clone formation experiments to study the effect of ATO on the proliferation of PC3 cells. Flow cytometry and Hoechst 33342 staining were used to detect cell apoptosis. Cell migration and invasion were detected through wound healing experiments and transwell experiments. Western blotting was applied to detect apoptosis-related proteins (BAX, Bcl-2, PARP, and Caspase-3), epithelial-mesenchymal transformation (EMT) proteins, and matrix metalloproteinase (MMP) expression. A mouse xenograft tumor model was established, and tumor volume and weight were determined. The expression levels of the above-mentioned proteins were determined through western blot. RESULTS: ATO inhibited PC-3 cell proliferation and promoted cell apoptosis in a dose-dependent manner. ATO significantly up-regulated the expression of BAX, PARP, and Caspase-3 and inhibited the expression of Bcl-2. Wound healing and transwell experiments showed that ATO inhibited invasion and metastasis in PC-3 cells, possibly because ATO could inhibit the EMT and the expression of MMPs in PC-3 cells. Studies in nude mice showed that ATO significantly reduced tumor volume and weight; the expression levels of related proteins were consistent with the in vitro results. CONCLUSIONS: ATO inhibits the occurrence and development of PCa and regulates the migration and invasion of PCa cells by inhibiting the EMT and MMPs.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias da Próstata , Animais , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Caspase 3/farmacologia , Caspase 3/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Metaloproteinases da Matriz , Camundongos , Camundongos Nus , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/patologia , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia
3.
Bratisl Lek Listy ; 123(5): 366-371, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35420883

RESUMO

AIM: Glucosamine derivatives have been found to have anticancer effects in many cancer cell lines in previous investigations. The effect of glucosamine sulfate on neuroblastoma, however, is uncertain. The potential cytotoxic effects of glucosamine sulfate on the SH-SY5Y cell line were investigated in this study. The underlying mechanisms of this cytotoxicity have also been studied. MATERIAL AND METHODS: In this study, the SH-SY5Y cell lines were used. The cells were treated with various concentrations of glucosamine sulfate (0.3125, 0.625, 1.25 and 2.5 µg/mL) and the viability of the cells was determined using the XTT assay after 24 hours. The quantities of cleaved PARP, BCL-2, 8-Hydroxy-desoxyguanosine (8-oxo-dG), cleaved caspase 3, Bax, total oxidant, and total antioxidant in the cells were determined by ELISA kits. RESULTS: At doses of 0.3125, 0.625, 1.25 and 2.5 µg/mL, glucosamine sulfate dramatically reduced cell viability in SH-SY5Y cells (p<0.001). ELISA tests demonstrated that 1.25 µg/mL glucosamine sulfate considerably increased the amounts of 8-oxo-dG, cleaved caspase 3, Bax, cleaved PARP and total oxidant. However, 1.25 µg/mL glucosamine sulfate treatment did not change the quantity of BCL-2 protein. CONCLUSIONS: Altogether, glucosamine sulfate produced considerable cytotoxicity in SH-SY5Y cells by triggering oxidative stress, inducing DNA damage, and finally causing apoptosis. In addition, more research is needed to determine the efficacy of glucosamine sulfate as an anticancer drug in the treatment of neuroblastoma (Fig. 5, Ref. 39).


Assuntos
Antineoplásicos , Neuroblastoma , 8-Hidroxi-2'-Desoxiguanosina , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Glucosamina/farmacologia , Glucosamina/uso terapêutico , Humanos , Neuroblastoma/tratamento farmacológico , Oxidantes/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Proteína X Associada a bcl-2
4.
PLoS One ; 17(4): e0267543, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35486574

RESUMO

BACKGROUND AND PURPOSE: PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 ß-emitting 177Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines. MATERIALS AND METHODS: The combined effect of 177Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes. RESULTS: The combination of olaparib and 177Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment. CONCLUSION: The cytotoxic effect of the combination of the PARP inhibitor olaparib and the ß-emitting radioimmunoconjugate 177Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines.


Assuntos
Antineoplásicos , Linfoma não Hodgkin , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Radioimunoterapia
5.
Cells ; 11(8)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35455964

RESUMO

Alzheimer's disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the ß-amyloid (Aß) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, we combined genetic, molecular and biochemical approaches to investigate the effects of two different PARP-1 inhibitors (olaparib and MC2050) in Drosophila models of Alzheimer's disease by exploring their neuroprotective and therapeutic potential in vivo. We found that both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aß42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, olaparib and MC2050 also suppress the AD-associated aberrant activation of transposable elements in neuronal tissues of AD flies.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Drosophila/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
6.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457012

RESUMO

MicroRNA (miRNA) acts as a critical regulator of growth in various human malignancies. However, the role of miRNA-3614 in the progression of human prostate cancer remains unknown. In this study, our results demonstrated that miRNA-3614-5p exerts a significant inhibitory effect on cell viability and colony formation and induces sub-G1 cell cycle arrest and apoptosis in human prostate cancer cells. Myeloid cell leukemia-1 (Mcl-1) acts as a master regulator of cell survival. Using the miRNA databases, miRNA-3614-5p was found to regulate Mcl-1 expression by targeting positions of the Mcl-1-3' UTR. The reduction of Mcl-1 expression by miRNA-3614-5p was further confirmed using an immunoblotting assay. Pro-apoptotic caspase-3 and poly (ADP-ribose) polymerase (PARP) were significantly activated by miRNA-3614-5p to generate cleaved caspase-3 (active caspase-3) and cleaved PARP (active PARP), accompanied by the inhibited Mcl-1 expression. These findings were the first to demonstrate the anti-growth effects of miRNA-3614-5p through downregulating Mcl-1 expression in human prostate cancer cells.


Assuntos
MicroRNAs , Neoplasias da Próstata , Apoptose , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Masculino , MicroRNAs/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/metabolismo
7.
Bioorg Med Chem ; 61: 116739, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35393219

RESUMO

The therapeutic strategy of poly (ADP-ribose) polymerase (PARP) inhibition of BRCA1/2 mutant cancers has been overwhelmingly successful, however, the highly aggressive triple negative breast cancers (TNBC) that receptor protein tyrosine kinase (RTKs) is known to be overexpressed are not sensitive to PARP inhibitors. Our research focused on exploring PARP inhibitors incorporating a bicyclic tetrahydropyridine pyrimidine. All synthesized compounds were more potent than Olaparib (ola) in killing tumor cells, especially in TNBC. Furthermore, compound 7 exhibited strong inhibitory effects on PARP enzymatic activity, moreover, the expression of EGFR and phosphorylated EGFR was inhibited by compound 7. Therefore, compound 7 can effectively inhibit TNBC cells with high expression of EGFR. In addition, significant synergistic effect of anti-tumor effect of new PARP inhibitors and adriamycin was also observed.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Mama Triplo Negativas , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Receptores ErbB , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Cancer Res ; 82(8): 1646-1657, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35425960

RESUMO

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies. SIGNIFICANCE: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Epitelial do Ovário/genética , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Recombinação Homóloga/genética , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Rad51 Recombinase/genética
9.
Biochem Biophys Res Commun ; 607: 89-95, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-35367833

RESUMO

DNA repair processes represent attractive synthetic lethal targets because many cancers exhibit impaired DNA repair pathways, which leads to dependence on specific repair proteins. The finding that poly (ADP-ribose) polymerase (PARP)-1 inhibitors are highly effective against cancers with deficient homologous recombination highlights the potential of this approach. In hepatitis B viral (HBV) infection, degradation of the structural maintenance of the chromosome 5/6 (Smc5/6) complex, which plays a key role in repairing double-stranded DNA breaks by homologous recombination, is induced by HBV regulatory protein X (HBx). Here, we hypothesized that a deficiency in the Smc5/6 complex in HBV-associated hepatocellular carcinoma (HCC) increases susceptibility to PARP inhibitors via a deficiency in homologous recombination. We confirmed impaired double-stranded DNA break repair in HBx-expressing HCC cells using a sensitive reporter to monitor homologous recombination. Treatment with a PARP inhibitor was significantly more effective against HBx-expressing HCC cells, and overexpression of Smc5/6 prevented these effects. Overall, our results suggest that homologous recombination deficiency in HBV-associated HCC leads to increased susceptibility to PARP inhibitors.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Recombinação Homóloga , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética
10.
Cancer Chemother Pharmacol ; 89(5): 683-695, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35419627

RESUMO

BACKGROUND: Although the use of PARP inhibitor has received considerable amount of attention in ovarian cancer, PARP inhibitor resistance still emerges with disease progression. PI3K/AKT pathway inhibitors have been proposed to synergize with PARP inhibition to slow tumor growth, but the exact molecular mechanisms are still elusive. METHODS: Utilizing tumor samples from recurrent EOC patients with platinum resistance and prior PARP inhibitor use, Mini PDX and PDX models were established to study the anti-tumor effect of AKT inhibitor (LAE003) and LAE003/PARP inhibitor (Olaparib) in combination. Five ovarian cancer cell lines were treated with Olaparib or LAE003 or in combination in vitro. Cell viability and apoptosis rate were measured after the treatments. Combination index by the Chou-Talalay was used to evaluate in vitro combination effect of Olaparib and LAE003. The protein expression level of PARP1 and PAR was measured by Western blot in cell lines and by immunohistochemistry in PDX tumor tissues. RESULTS: Tumor cells from two out of five platinum-resistant ovarian cancer patients previously treated with PARP inhibitor were sensitive to AKT inhibition in Mini-PDX study. Inhibition of AKT further increased the response of tumor cells to Olaparib in a PDX model derived from a recurrent platinum-resistant ovarian cancer patient. Additive anti-proliferation effect of LAE003 and Olaparib was also observed in three ovarian cancer cell lines with high PARP1 protein level. Interestingly, mechanism study revealed that AKT inhibition decreased PARP enzyme activity as measured by PAR level and/or reduced PARP1 protein level in the tumor cell lines and PDX tumor tissues, which may explain the observed combined anti-tumor effect of LAE003 and Olaparib. CONCLUSION: Collectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Med Rep ; 25(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35475506

RESUMO

It has been reported that oxidative stress plays a prominent role in diabetic macrovascular diseases. 3,4­Dihydroxyacetophenone (3,4­DHAP) has been found to have a variety of biological activities. However, few studies have assessed the antioxidant capacity of 3,4­DHAP and the underlying mechanisms. Thus, the aim of the present study was to explore the effects of 3,4­DHAP on oxidative stress in human umbilical vein endothelial cells (HUVECs). HUVECs were pre­treated with 3,4­DHAP and then exposed to high glucose conditions. Cell viability and cytotoxicity were measured using an MTT assay. Reactive oxygen species (ROS) levels were measured using an inverted fluorescence microscope and a fluorescent enzyme labeling instrument. Protein expression levels of nuclear factor E2­related factor 2 (Nrf2), heme oxygenase­1 (HO­1), microtubule­associated protein 1A/1B­light chain 3 (LC3) and poly ADP­ribose polymerase­1 (PARP­1) were measured using western blotting, and mRNA expression of Nrf2 and HO­1 were measured through reverse transcription­quantitative PCR (RT­qPCR). Nrf2 nuclear translocation was evaluated using immunofluorescence analysis and autophagosomes were observed using transmission electron microscope (TEM). The results of the present study demonstrated that compared with the control group, cell viability of the high glucose group was reduced and cell cytotoxicity of the high glucose group was increased. ROS production in the high glucose group was clearly enhanced. In addition, high glucose upregulated Nrf2 and HO­1 protein and mRNA expression levels. Nuclear translocation of Nrf2 in the high glucose group was also increased. The formation of autophagosomes in the high glucose group was also higher than that in the control group. Furthermore, LC3­II/LC3­I and PARP­1 protein expression levels were increased after treatment with high glucose. However, compared to the high glucose group, 3,4­DHAP (10 µmol/l) significantly enhanced cell viability. 3,4­DHAP markedly decreased the production of ROS, increased Nrf2 and HO­1 protein and mRNA expression levels, and promoted nuclear translocation of Nrf2 in HUVECs. In addition, 3,4­DHAP promoted the formation of autophagosomes, and notably increased the protein expression levels of LC3­II/LC3­I and PARP­1. Moreover, it was determined that compared to the 3,4­DHAP group, treatment with 3,4­DHAP and ML385 enhanced cell viability, and decreased ROS production, Nrf2 and HO­1 protein and mRNA expression levels, nuclear translocation of Nrf2, and LC3­II/LC3­I and PARP­1 protein expression levels. Collectively, the results of the present study showed that 3,4­DHAP protected HUVECs against oxidative stress via regulation of the Nrf2/HO­1 pathway, by increasing autophagy and promoting DNA damage repair.


Assuntos
Heme Oxigenase-1 , Fator 2 Relacionado a NF-E2 , Acetofenonas , Glucose/metabolismo , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Cells ; 11(8)2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35456022

RESUMO

Herein, the apoptotic mechanism of 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose (PGG) was examined in cisplatin-resistant lung cancer cells. PGG significantly reduced viability; increased sub-G1 accumulation and the number of terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL)-positive cells; induced the cleavage of poly (ADP-ribose) polymerase (PARP), caspases (8,9,3,7), B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN); and attenuated the expression of p-AKT, X-linked inhibitor of apoptosis protein (XIAP), Bcl-2, Bcl-xL and survivin in A549/cisplatin-resistant (CR) and H460/CR cells. Notably, PGG activated p53, p-checkpoint kinase 2 (CHK2) and p-H2A histone family member X (p-H2AX), with increased levels of DNA damage (DSBs) evaluated by highly expressed pH2AX and DNA fragmentation registered on comet assay, while p53 knockdown reduced the ability of PGG to reduce viability and cleave caspase 3 and PARP in A549/CR and H460/CR cells. Additionally, PGG treatment suppressed the growth of H460/CR cells in Balb/c athymic nude mice with increased caspase 3 expression compared with the cisplatin group. Overall, PGG induces apoptosis in cisplatin-resistant lung cancer cells via the upregulation of DNA damage proteins such as γ-H2AX, pCHK2 and p53.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Neoplasias Pulmonares , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2/metabolismo , Cisplatino/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Glucose , Humanos , Taninos Hidrolisáveis , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Fosforilação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo
13.
Biochem Pharmacol ; 199: 115024, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35367197

RESUMO

The efficacy of poly (ADP-ribose) polymerase inhibitors (PARPi) is largely limited to the homologous recombination (HR) deficient cancers. Therefore, there is a necessity to explore novel drug combinations with PARPi to enhance its anti-cancer activity in HR-proficient cancers. By analysing the patient data in cBioPortal, we found copy number amplification of PARP1 in âˆ¼ 22.8% of breast cancers. PARP1 upregulation has been correlated with unfavourable outcome with PARPi treatment. To overcome this adversity, we explored the effect of resveratrol, a natural molecule chemosensitizer, in enhancing the effects of the third generation PARPi, talazoparib (BMN673), against breast adenocarcinoma. Our results show that resveratrol effectively sensitized talazoparib induced cell death in HR proficient and BRCA wild-type breast cancer cells in vitro. Mechanistically, resveratrol caused dysregulation of cell cycle and enhanced talazoparib-induced double strand breaks (DSBs), leading to abnormal mitotic progression culminating in mitotic catastrophe. Intriguingly, our results showed potential of resveratrol in dual-inhibition of AKT-signalling and autophagy flux to impair HR-mediated DSB-repair in breast cancer cells. By using EGFP-LC3 and tf-LC3 (mRFP-EGFP-LC3) expressing breast cancer cells, we found that resveratrol attenuates fusion of autophagosome and lysosome though induction of lysosomal-membrane-permeabilization (LMP). The combination of resveratrol and talazoparib effectively reduced cell proliferation in the high-density cell proliferation assay and also led to tumour volume reduction in vivo pre-clinical SCID-mice model. The combination caused no or minimal cytotoxicity in three different normal cell lines in vitro. Taken together, our work proposes the usage of resveratrol as a chemosensitizer along with talazoparib for targeting HR-proficient breast cancers in clinical settings.


Assuntos
Antineoplásicos , Neoplasias da Mama , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Ann Surg Oncol ; 29(6): 3591-3592, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35391610

RESUMO

Poly(ADP-ribose) polymerase (PARP) inhibitors selectively cause the failure of DNA single-stranded break (SSB) repair but do not affect double-stranded break (DSB) repair. Furthermore, antitumor activities have been reported for breast cancer, with germline BRCA1/2 mutations. The prevalence of germline BRCA1/2 mutations never exceed one-tenth; beyond BRCA1/2, genes recurrently altered (more than 5%) in the homologous repair pathway are ARID1A, PALB2, and PTEN. Altered homologous recombination repair genes can total up to one-quarter based on different definitions, and the potential of PARP inhibitors will be elucidated when further studies unraveling the impact of individual homologous recombination genes are conducted.


Assuntos
Neoplasias da Mama , Mutações Sintéticas Letais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Reparo do DNA , Feminino , Recombinação Homóloga , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases
15.
Oncogene ; 41(19): 2706-2718, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35393543

RESUMO

DNA double-strand break (DSB) repair-pathway choice regulated by 53BP1 and BRCA1 contributes to genome stability. 53BP1 cooperates with the REV7-Shieldin complex and inhibits DNA end resection to block homologous recombination (HR) and affects the sensitivity to inhibitors for poly (ADP-ribose) polymerases (PARPs) in BRCA1-deficient cells. Here, we show that a REV7 binding protein, CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), has an opposite function of REV7 in DSB repair and promotes HR through DNA end resection together with POGZ (POGO transposable element with ZNF domain). CHAMP1 was recruited to laser-micro-irradiation-induced DSB sites and promotes HR, but not NHEJ. CHAMP1 depletion suppressed the recruitment of BRCA1, but not the recruitment of 53BP1, suggesting that CHAMP1 regulates DSB repair pathway in favor of HR. Depletion of either CHAMP1 or POGZ impaired the recruitment of phosphorylated RPA2 and CtIP (CtBP-interacting protein) at DSB sites, implying that CHAMP1, in complex with POGZ, promotes DNA end resection for HR. Furthermore, loss of CHAMP1 and POGZ restored the sensitivity to a PARP inhibitor in cells depleted of 53BP1 together with BRCA1. These data suggest that CHAMP1and POGZ counteract the inhibitory effect of 53BP1 on HR by promoting DNA end resection and affect the resistance to PARP inhibitors.


Assuntos
Quebras de DNA de Cadeia Dupla , Inibidores de Poli(ADP-Ribose) Polimerases , Proteína BRCA1/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , DNA/metabolismo , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Recombinação Homóloga , Humanos , Fosfoproteínas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transposases/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
16.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409229

RESUMO

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Carcinoma Epitelial do Ovário/tratamento farmacológico , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Mutação , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Microambiente Tumoral
17.
Curr Treat Options Oncol ; 23(6): 887-903, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35412195

RESUMO

OPINION STATEMENT: Poly-ADP-ribose polymerase inhibitors (PARPi) are a class of anti-cancer drugs that target DNA repair pathways and have shown promising efficacy in patients with ovarian cancer in recent clinical trials. To date, there have been 9 FDA PARPi approvals/indications in ovarian cancer since 2014, highlighting the importance of this class of agents in the treatment of ovarian cancer. BRCA1/2-mutated tumors or other forms of homologous recombination deficient (HRD) tumors are particularly susceptible to PARP inhibition and have seen the greatest benefits of improvement in response rate and progression-free survival (PFS) in clinical trials. Patients with homologous recombination-proficient tumors also receive benefit, especially when a nice response to paltinum is noted, but to a lesser extent. PARP inhibitors now have FDA approval and indications in first-line and recurrent maintenance, and treatment. PARP inhibitor use as maintenance therapy in the front-line setting is now considered the standard of care in patients with BRCA1/2 mutations based on the SOLO-1/GOG-3004/ENGOT study. PARP inhibitors are also recommended per ASCO guidelines in all patients with ovarian cancer as front-line maintenance therapy based on the PRIMA/ENGOT-OV26/GOG-3012 trial. The combination of PARP inhibitor, olaparib, and the anti-angiogenesis inhibitor bevacizumab is also approved as maintenance therapy after front-line chemotherapy treatment in patients with HRD tumors and is an option for patients who have initiated bevacizumab with their chemotherapy treatment. PARPi are also FDA approved and can be utilized as a treatment in third-line and beyond in recurrent ovarian cancer patients with BRCA1/2 mutations and HRD tumors. In this review, we will cover in detail when PARP inhibitor use is appropriate in ovarian cancer, as well as the various clinical factors to take into consideration when selecting a PARP inhibitor regimen.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
18.
Mol Cancer Ther ; 21(4): 647-657, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35373300

RESUMO

High-grade serous ovarian cancer is the deadliest gynecologic malignancy due to progression to resistant disease. Claudin-4 is classically defined as a tight junction protein and is often associated with epithelial cancers. Claudin-4 is aberrantly expressed in nearly 70% of all ovarian cancer tumors and conveys a worse overall prognosis. Elevated claudin-4 expression correlates to increased DNA repair activity and resistance to DNA damaging agents. PARP inhibitors are emerging as an effective therapeutic option for patients with ovarian cancer and function by promoting DNA damage. The study examines the relationship between claudin-4 expression and the response to PARP inhibitors using both genetic and pharmacologic inhibition of claudin-4 in in vitro and ex vivo models of ovarian cancer to examine DNA repair markers and functional activity. Genetic inhibition of claudin-4 results in the downregulation of several DNA damage repair effectors, including 53BP1 and XRCC1. Claudin-4 knockdown did not change homology-directed repair but inhibited nonhomologous end-joining and reduced 53BP1 foci formation. In 15 primary ovarian cancer tumors, higher claudin-4 expression significantly correlated to a dampened PARP inhibitor-mediated antiproliferation response. Further, claudin-4 inhibition in high claudin-4 tumors sensitized tumor sections to PARP inhibition. These data highlight that claudin-4 expression in ovarian cancer tumors could serve as both a marker of PARP inhibitor response and a therapeutic target to improve PARP inhibitor response.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Claudina-4/genética , Dano ao DNA , Reparo do DNA , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
19.
Epigenetics Chromatin ; 15(1): 11, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35382873

RESUMO

BACKGROUND: Poly(ADP-ribosyl)ation (PARylation), a posttranslational modification introduced by PARP-1 and PARP-2, has first been implicated in DNA demethylation due to its role in base excision repair. Recent evidence indicates a direct influence of PARP-dependent PARylation on TET enzymes which catalyse hydroxymethylation of DNA-the first step in DNA demethylation. However, the exact nature of influence that PARylation exerts on TET activity is still ambiguous. In our recent study, we have observed a negative influence of PARP-1 on local TET-mediated DNA demethylation of a single gene and in this study, we further explore PARP-TET interplay. RESULTS: Expanding on our previous work, we show that both TET1 and TET2 can be in vitro PARylated by PARP-1 and PARP-2 enzymes and that TET1 PARylation negatively affects the TET1 catalytic activity in vitro. Furthermore, we show that PARylation inhibits TET-mediated DNA demethylation at the global genome level in cellulo. CONCLUSIONS: According to our findings, PARP inhibition can positively influence TET activity and therefore affect global levels of DNA methylation and hydroxymethylation. This gives a strong rationale for future examination of PARP inhibitors' potential use in the therapy of cancers characterised by loss of 5-hydroxymethylcytosine.


Assuntos
Poli ADP Ribosilação , Inibidores de Poli(ADP-Ribose) Polimerases , DNA/metabolismo , Metilação de DNA , Reparo do DNA , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
20.
Cell Death Dis ; 13(3): 263, 2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332131

RESUMO

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Animais , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...