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1.
Nat Commun ; 12(1): 5224, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471130

RESUMO

The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood. Here, we report the characterization of a chromatin remodeling enzyme-Yta7-entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA+ -ATPase that assembles into ~1 MDa hexameric complexes capable of segregating histones from DNA. The Yta7 chromatin segregase promotes chromosome replication both in vivo and in vitro. Biochemical reconstitution experiments using purified proteins revealed that the enzymatic activity of Yta7 is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication. Our results present a mechanism for how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Replicação do DNA/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Adenosina Trifosfatases/metabolismo , Pontos de Checagem do Ciclo Celular , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , DNA/metabolismo , Histonas/metabolismo , Humanos , Fosforilação , Fase S , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição
2.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500557

RESUMO

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Mebendazol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
3.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500621

RESUMO

Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 µg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors' knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Venenos de Cnidários/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Cifozoários/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(9): 794-800, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34533126

RESUMO

Objective To investigate the effect of endoplasmic reticulum stress (ERS) induced by tunicamycin on proliferation, activation, and apoptosis of HSC-T6 rat hepatic stellate cells and its possible mechanism. Methods With the expression level of glucose regulated protein 78 (GRP78) as an indicator to explore the optimal concentration and time, a cell model of tunicamycin-induced ERS in HSC-T6 cells was established. HSC-T6 cells were randomized into control group, treatment group with 1 mL/L of dimethyl sulfoxide (DMSO), and treatment group with 1 µg/mL of tunicamycin, and the cells were treated for 12 h. MTT assay was used to detect cell proliferation, flow cytometry to detect apoptosis and cell cycle, and Western blot to detect the protein expressions of α-smooth muscle actin (α-SMA), C/EBP cAMP homologous protein (CHOP), caspase-12, and cyclin D1. Results The optimal dose of tunicamycin to induce ERS in HSC-T6 cells was 1 µg/mL and the optimal time was 12 hours. Compared with the control group and treatment group with DMSO, the treatment group with 1 µg/mL of tunicamycin had no significant change in cell proliferation, but the expression of α-SMA was up-regulated with the apoptosis increased, the proportion of G1 phase cells was significantly increased and that of S phase cells decreased, the ERS induced apoptosis related signal proteins CHOP and caspase-12 were significantly up-regulated, and the expression of cyclin D1 was significantly down-regulated. Conclusion Tunicamycin treatment of HSC-T6 cells for 12 hours induces significant ERS and activation of the cells. The insignificant change in the number of cells during the activation may be related to the increased apoptosis and the cell cycle arrest induced by the activation of the GRP78/CHOP/caspase-12 pathway.


Assuntos
Estresse do Retículo Endoplasmático , Células Estreladas do Fígado , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Ratos , Tunicamicina/farmacologia
5.
Nat Commun ; 12(1): 5505, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535668

RESUMO

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.


Assuntos
Proteína DEAD-box 58/metabolismo , Imunidade Inata , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fator Regulador 1 de Interferon/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Oncogenes , Transdução de Sinais/efeitos dos fármacos
6.
Nanoscale ; 13(34): 14525-14537, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473816

RESUMO

Radiotherapy (RT) is one of the main treatments for men with prostate cancer (PCa). To date, numerous sophisticated nano-formulations as radiosensitizers have been synthesized with inspiring therapeutic effects both in vitro and in vivo; however, almost all the attention has been paid on the enhanced dose deposition effect by secondary electrons of nanomaterials with high atomic numbers (Z); despite this, cell-cycle arrest, DNA damage, and also reactive oxygen species (ROS) production are critical working mechanisms that account for radiosensitization. Herein, an 'all-purpose' nanostrategy based on dose deposition enhancement, cell cycle arrest, and ROS production as prostate cancer radiosensitizer for potential clinical translation was proposed. The rather simple structure of docetaxel-loaded Au nanoparticles (NPs) with prostate specific membrane antigen (PSMA) ligand conjugation have been successfully synthesized. Enhanced cellular uptake achieved via the selective internalization of the NPs by PCa cells with positive PSMA expression could guarantee enhanced dose deposition. Moreover, the as-synthesized nanosystem could effectively arrest the cell cycle at G2/M phases, which would reduce the ability of DNA damage repair for more irradiation sensitive of the PCa cells. Moreover, the G2/M phase arrest would further promote cascade retention and the enrichment of NPs within the cells. Furthermore, ROS generation and double strand breaks greatly promoted by NPs under irradiation (IR) could also provide an underlying basis for effective radiosensitizers. In vitro and in vivo investigations confirmed the as-synthesized NPs as an effective nano-radiosensitizer with ideal safety. More importantly, all moieties within the present nanosystem have been approved by FDA for the purpose of PCa treatment, thus making it highly attractive for clinical translation.


Assuntos
Nanopartículas Metálicas , Neoplasias da Próstata , Pontos de Checagem do Ciclo Celular , Dano ao DNA , Ouro , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Espécies Reativas de Oxigênio
7.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500594

RESUMO

Lung cancer is the most commonly diagnosed malignant cancer in the world. Non-small-cell lung cancer (NSCLC) is the major category of lung cancer. Although effective therapies have been administered, for improving the NSCLC patient's survival, the incident rate is still high. Therefore, searching for a good strategy for preventing NSCLC is urgent. Traditional Chinese medicine (TCM) are brilliant materials for cancer chemoprevention, because of their high biological safety and low cost. Bavachinin, which is an active flavanone of Proralea corylifolia L., possesses anti-inflammation, anti-angiogenesis, and anti-cancer activities. The present study's aim was to evaluate the anti-cancer activity of bavachinin on NSCLC, and its regulating molecular mechanisms. The results exhibited that a dose-dependent decrease in the cell viability and colony formation capacity of three NSCLC cell lines, by bavachinin, were through G2/M cell cycle arrest induction. Meanwhile, the expression of the G2/M cell cycle regulators, such as cyclin B, p-cdc2Y15, p-cdc2T161, and p-wee1, was suppressed. With the dramatic up-regulation of the cyclin-dependent kinase inhibitor, p21Waf1/Cip1, the expression and association of p21Waf1/Cip1 with the cyclin B/cdc2 complex was observed. Silencing the p21Waf1/Cip1 expression significantly rescued bavachinin-induced G2/M cell accumulation. Furthermore, the expression of p21Waf1/Cip1 mRNA was up-regulated in bavachinin-treated NSCLC cells. In addition, MAPK and AKT signaling were activated in bavachinin-added NSCLC cells. Interestingly, bavachinin-induced p21Waf1/Cip1 expression was repressed after restraint p38 MAPK activation. The inhibition of p38 MAPK activation reversed bavachinin-induced p21Waf1/Cip1 mRNA expression and G2/M cell cycle arrest. Collectively, bavachinin-induced G2/M cell cycle arrest was through the p38 MAPK-mediated p21Waf1/Cip1-dependent signaling pathway in the NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Flavonoides/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Células A549 , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1 , Inibidor de Quinase Dependente de Ciclina p21/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Humanos , Neoplasias Pulmonares/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360883

RESUMO

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Suplementos Nutricionais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Valeratos/farmacologia , Adenocarcinoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo
9.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360748

RESUMO

Research on the budding yeast Saccharomyces cerevisiae has yielded fundamental discoveries on highly conserved biological pathways and yeast remains the best-studied eukaryotic cell in the world. Studies on the mitotic cell cycle and the discovery of cell cycle checkpoints in budding yeast has led to a detailed, although incomplete, understanding of eukaryotic cell cycle progression. In multicellular eukaryotic organisms, uncontrolled aberrant cell division is the defining feature of cancer. Some of the most successful classes of anti-cancer chemotherapeutic agents are mitotic poisons. Mitotic poisons are thought to function by inducing a mitotic spindle checkpoint-dependent cell cycle arrest, via the assembly of the highly conserved mitotic checkpoint complex (MCC), leading to apoptosis. Even in the presence of mitotic poisons, some cancer cells continue cell division via 'mitotic slippage', which may correlate with a cancer becoming refractory to mitotic poison chemotherapeutic treatments. In this review, knowledge about budding yeast cell cycle control is explored to suggest novel potential drug targets, namely, specific regions in the highly conserved anaphase-promoting complex/cyclosome (APC/C) subunits Apc1 and/or Apc5, and in a specific N-terminal region in the APC/C co-factor cell division cycle 20 (Cdc20), which may yield molecules which block 'mitotic slippage' only in the presence of mitotic poisons.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Pontos de Checagem do Ciclo Celular , Mitose , Neoplasias , Saccharomyces cerevisiae , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mitose/efeitos dos fármacos , Mitose/genética , Neoplasias/genética , Neoplasias/metabolismo , Venenos/química , Venenos/farmacologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
10.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361036

RESUMO

Hinokitiol is a natural tropolone derivative that is present in the heartwood of cupressaceous plants, and has been extensively investigated for its anti-inflammatory, antioxidant, and antitumor properties in the context of various diseases. To date, the effects of hinokitiol on endometrial cancer (EC) has not been explored. The purpose of our study was to investigate the anti-proliferative effects of hinokitiol on EC cells. Cell viability was determined with an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the quantification of apoptosis and reactive oxygen species (ROSs) was performed by using flow cytometry, while protein expression was measured with the Western blotting technique. Hinokitiol significantly suppressed cell proliferation through the inhibition of the expression of cell-cycle mediators, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the induction of the tumor suppressor protein p53. In addition, hinokitiol increased the number of apoptotic cells and increased the protein expression of cleaved-poly-ADP-ribose polymerase (PARP) and active cleaved-caspase-3, as well as the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2). Interestingly, except for KLE cells, hinokitiol induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and reducing the sequestosome-1 (p62/SQSTM1) protein level. Furthermore, hinokitiol triggered ROS production and upregulated the phosphorylation of extracellular-signal-regulated kinase (p-ERK1/2) in EC cells. These results demonstrate that hinokitiol has potential anti-proliferative and pro-apoptotic benefits in the treatment of endometrial cancer cell lines (Ishikawa, HEC-1A, and KLE).


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Apoptose , Pontos de Checagem do Ciclo Celular , Neoplasias do Endométrio/metabolismo , Monoterpenos/toxicidade , Tropolona/análogos & derivados , Autofagia , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tropolona/toxicidade , Proteína Supressora de Tumor p53/metabolismo
11.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443472

RESUMO

Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estirenos/farmacologia , Antineoplásicos/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/química , Curcumina/metabolismo , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Fase G2/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenol/química , Fenol/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Estirenos/química , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/agonistas
12.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443411

RESUMO

Several novel methyl 7-[(hetero)arylamino]thieno[2,3-b]pyrazine-6-carboxylates were synthesized by Pd-catalyzed C-N Buchwald-Hartwig cross-coupling of either methyl 7-aminothieno[3,2-b]pyrazine-6-carboxylate with (hetero)arylhalides or 7-bromothieno[2,3-b]pyrazine-6-carboxylate with (hetero)arylamines in good-to-excellent yields (50% quantitative yield), using different reaction conditions, namely ligands and solvents, due to the different electronic character of the substrates. The antitumoral potential of these compounds was evaluated in four human tumor cell lines: gastric adenocarcinoma (AGS), colorectal adenocarcinoma (CaCo-2), breast carcinoma (MCF7), and non-small-cell lung carcinoma (NCI-H460) using the SRB assay, and it was possible to establish some structure-activity relationships. Furthermore, they did not show relevant toxicity against a non-tumor cell line culture from the African green monkey kidney (Vero). The most promising compounds (GI50 ≤ 11 µM), showed some selectivity either against AGS or CaCo-2 cell lines without toxicity at their GI50 values. The effects of the methoxylated compounds 2b (2-OMeC6H4), 2f and 2g (3,4- or 3,5-diOMeC6H3, respectively) on the cell cycle profile and induction of apoptosis were further studied in the AGS cell line. Nevertheless, even for the most active (GI50 = 7.8 µM) and selective compound (2g) against this cell line, it was observed that a huge number of dead cells gave rise to an atypical distribution on the cell cycle profile and that these cells were not apoptotic, which points to a different mechanism of action for the AGS cell growth inhibition.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Pontos de Checagem do Ciclo Celular , Pirazinas/síntese química , Pirazinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pirazinas/química
13.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443415

RESUMO

MiR-34a, an important tumor suppressor, has been demonstrated to possess great potential in tumor gene therapy. To achieve the upregulation of miR-34a expression level, an oligoethyleneimine (OEI) derivative was constructed and employed as the carrier through the modification with lipoic acid (LA), namely LA-OEI. In contrast to OEI, the derivative LA-OEI exhibited superior transfection efficiency measured by confocal laser scanning microscopy and flow cytometry, owing to rapid cargo release in the disulfide bond-based reduction sensitive pattern. The anti-proliferation and anti-migration effects were tested after the miR-34a transfection to evaluate the anti-tumor response, using human cervical carcinoma cell line HeLa as a model. The delivery of LA-OEI/miR-34a nanoparticles could achieve obvious anti-proliferative effect caused by the induction of cell apoptosis and cell cycle arrest at G1 phase. In addition, it could inhibit the migration of tumor cells via the downregulation of MMP-9 and Notch-1 level. Overall, the LA-OEI-mediated miR-34a delivery was potential to be used as an effective way in the tumor gene therapy.


Assuntos
Antineoplásicos/farmacologia , MicroRNAs/metabolismo , Polietilenoimina/química , Ácido Tióctico/química , Transfecção , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , MicroRNAs/genética , Nanopartículas/ultraestrutura , Polietilenoimina/síntese química , Ácido Tióctico/síntese química , Cicatrização/efeitos dos fármacos
14.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443427

RESUMO

Pterostilbene, a natural metabolite of resveratrol, has been indicated as a potent anticancer molecule. Recently, several pterostilbene derivatives have been reported to exhibit better anticancer activities than that of the parent pterostilbene molecule. In the present study, a series of pterostilbene derivatives were designed and synthesized by the hybridization of pterostilbene, chalcone, and cinnamic acid. The cytotoxic effect of these hybrid molecules was determined using two oral cancer cell lines, HSC-3 and OECM-1. (E)-3-(2-((E)-4-Hydroxystyryl)-4,6-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (4d), with IC50 of 16.38 and 18.06 µM against OECM-1 and HSC-3, respectively, was selected for further anticancer mechanism studies. Results indicated that compound 4d effectively inhibited cell proliferation and induced G2/M cell cycle arrest via modulating p21, cyclin B1, and cyclin A2. Compound 4d ultimately induced cell apoptosis by reducing the expression of Bcl-2 and surviving. In addition, cleavage of PARP and caspase-3 were enhanced following the treatment of compound 4d with increased dose. To conclude, a number of pterostilbene derivatives were discovered to possess potent anticancer potentials. Among them, compound 4d was the most active, more active than the parent pterostilbene.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Estilbenos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Poli(ADP-Ribose) Polimerases/metabolismo , Estilbenos/química , Relação Estrutura-Atividade
15.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443490

RESUMO

Hydroxycamptothecin (SN38) is a natural plant extract isolated from Camptotheca acuminate. It has a broad spectrum of anticancer activity through inhibition of DNA topoisomerase I, which could affect DNA synthesis and lead to DNA damage. Thus, the action of SN38 against cancers could inevitably affect endogenous levels of ribonucleotide (RNs) and deoxyribonucleotide (dRNs) that play critical roles in many biological processes, especially in DNA synthesis and repair. However, the exact impact of SN38 on RNs and dRNs is yet to be fully elucidated. In this study, we evaluated the anticancer effect and associated mechanism of SN38 in human colorectal carcinoma HCT 116 cells. As a result, SN38 could decrease the cell viability and induce DNA damage in a concentration-dependent manner. Furthermore, cell cycle arrest and intracellular nucleotide metabolism were perturbed due to DNA damage response, of which ATP, UTP, dATP, and TTP may be the critical metabolites during the whole process. Combined with the expression of deoxyribonucleoside triphosphates synthesis enzymes, our results demonstrated that the alteration and imbalance of deoxyribonucleoside triphosphates caused by SN38 was mainly due to the de novo nucleotide synthesis at 24 h, and subsequently the salvage pathways at 48 h. The unique features of SN38 suggested that it might be recommended as an effective supplementary drug with an anticancer effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , DNA/metabolismo , Ribonucleotídeos/metabolismo , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Células HCT116 , Humanos , Irinotecano/farmacologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleotídeo Redutases/metabolismo
16.
Nutrients ; 13(8)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34444715

RESUMO

The traditional Mediterranean Diet constitutes a food model that refers to the dietary patterns of the population living in countries bordering the Mediterranean Sea in the early 1960s. A huge volume of literature data suggests that the Mediterranean-style diet provides several dietary compounds that have been reported to exert beneficial biological effects against a wide spectrum of chronic illnesses, such as cardiovascular and neurodegenerative diseases and cancer including breast carcinoma. Among bioactive nutrients identified as protective factors for breast cancer, natural polyphenols, retinoids, and polyunsaturated fatty acids (PUFAs) have been reported to possess antioxidant, anti-inflammatory, immunomodulatory and antitumoral properties. The multiple anticancer mechanisms involved include the modulation of molecular events and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, antioxidant enzymes and immune responses. This review summarizes the anticancer action of some polyphenols, like resveratrol and epigallocatechin 3-gallate, retinoids and omega-3 PUFAs by highlighting the important hallmarks of cancer in terms of (i) cell cycle growth arrest, (ii) apoptosis, (iii) inflammation and (iv) angiogenesis. The data collected from in vitro and in vivo studies strongly indicate that these natural compounds could be the prospective candidates for the future anticancer therapeutics in breast cancer disease.


Assuntos
Antineoplásicos , Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Dieta Mediterrânea , Suplementos Nutricionais , Animais , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/patologia , Catequina/análogos & derivados , Catequina/farmacologia , Pontos de Checagem do Ciclo Celular , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Inflamação , Polifenóis/farmacologia , Resveratrol/farmacologia , Retinoides/farmacologia
17.
Life Sci ; 284: 119907, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453950

RESUMO

AIMS: This study aimed at investigating the role of Brusatol (BR) on human laryngeal squamous carcinoma cell (Hep-2) to study its underlying mechanism through in vitro and in vivo approaches. MATERIALS AND METHOD: In the present research, we employed various cell-based assays, such as cell proliferation, apoptosis, cell cycle assessment, migration and invasion assays were used to examine the anti-tumor effect of BR on Hep-2 cells. Immunohistochemistry (IHC), qRT-PCR and Western blotting were performed to study the underlying molecular mechanisms. To validate our in vitro findings we used a subcutaneous tumor-bearing model of Balb/c mice with Hep-2 cells of laryngeal carcinoma (LC) to study the inhibitory effect of BR on Hep-2 cells in vivo. KEY FINDINGS: The results indicated that BR markedly inhibited the viability, migration and invasion capacity of Hep-2 cells, with no significant toxic effect on normal Human bronchial epithelial cell line (BEAS-2B). Also, BR induced cellular apoptosis by blocking the cells in S phase to suppress cell proliferation. Immunohistochemistry results revealed that BR inhibited the protein expression levels of epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, western blotting results exhibited that BR could suppress the protein expression of both JAK2/STAT3 and their phosphorylation levels. Our in vivo experiments further validated the anti-tumor effect of BR on Hep-2 cells in vitro, where BR suppressed the growth of xenograft laryngeal tumor without apparent toxicity. SIGNIFICANCE: The present study highlights the anti-LC effect of BR by possibly abrogating JAK2/STAT3 signaling mediated EMT process. BR may be a promising therapeutic candidate for the treatment of LC.


Assuntos
Transição Epitelial-Mesenquimal , Janus Quinase 2/metabolismo , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Quassinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Laríngeas/genética , Masculino , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Quassinas/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase S/efeitos dos fármacos , Fase S/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Eur J Med Chem ; 223: 113730, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34388483

RESUMO

Alterations in lipid metabolism, commonly disregarded in the past, have been accepted as a hallmark for cancer. Exploring cancer therapeutics that interrupt the lipid metabolic pathways by monotherapy or combination with conventional chemotherapy or immunotherapy is of great importance. Here we modified cisplatin with an FDA-approved hypolipidemic drug, bezafibrate (BEZ), via the well-established Pt(IV) strategy, affording two multi-functional Pt(IV) anticancer agents cis,cis,trans-[Pt(NH3)2Cl2(BEZ)(OH)] (CB) and cis,cis,trans-[Pt(NH3)2Cl2(BEZ)2] (CP) (BEZ = bezafibrate). The Pt(IV) prodrug CB exhibited an enhanced anticancer activity up to 187-fold greater than the clinical anticancer drug cisplatin. Both CB and CP had less toxicity to normal cells, showing higher efficacies and superior therapeutic indexes than cisplatin. Mechanism studies revealed that the bezafibrate-conjugated Pt(IV) complex CB, as a representative, could massively accumulate in A549 cells and genomic DNA, induce DNA damage, elevate intracellular ROS levels, perturb mitochondrial transmembrane potentials, activate the cellular metabolic sensor AMPK, and result in profound proliferation inhibition and apoptosis. Further cellular data also provided evidence that phosphorylation of AMPK, as a metabolic sensor, could suppress the downstream HMGB1, NF-κB, and VEGFA, which may contribute to the inhibition of angiogenesis and metastasis. Our study suggests that the antitumor action of CB and CP mechanistically distinct from the conventional platinum drugs and that functionalizing platinum-based agents with lipid-modulating agents may represent a novel practical strategy for cancer treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Bezafibrato/química , Hipolipemiantes/química , Platina/química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pró-Fármacos/farmacologia , Transdução de Sinais/efeitos dos fármacos
19.
Am J Physiol Renal Physiol ; 321(4): F431-F442, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34396791

RESUMO

The proximal tubule (PT) is highly vulnerable to acute injury, including ischemic insult and nephrotoxins, and chronic kidney injury. It has been established that PT injury is a primary cause of the development of chronic kidney disease, but the underlying molecular mechanism remains to be defined. Here, we tested whether PT cyclophilin D (CypD), a mitochondrial matrix protein, is a critical factor to cause kidney fibrosis progression. To define the role of CypD in kidney fibrosis, we used an established mouse model for kidney fibrosis: the unilateral ureteral obstruction (UUO) model in global and PT-specific CypD knockout (KO). Global CypD KO blunted kidney fibrosis progression with inhibition of myofibroblast activation and fibrosis. UUO-induced tubular atrophy was suppressed in kidneys of global CypD KO but not tubular dilation or apoptotic cell death. PT cell cycle arrest was highly increased in wild-type UUO kidneys but was markedly attenuated in global CypD KO UUO kidneys. The number of macrophages and neutrophils was less in UUO kidneys of global CypD KO than those of wild-type kidneys. Proinflammatory and profibrotic factors were all inhibited in global CypD KO. In line with those of global CypD KO, PT-specific CypD KO also blunted kidney fibrosis progression, along with less tubular atrophy, renal parenchymal loss, cell cycle arrest in PT, and inflammation, indicating a critical role for PT CypD in fibrogenesis. Collectively, our data demonstrate that CypD in the PT is a critical factor contributing to kidney fibrosis in UUO, providing a new paradigm for mitochondria-targeted therapeutics of fibrotic diseases.NEW & NOTEWORTHY It has been established that renal proximal tubule (PT) injury is a primary cause of the development of chronic kidney disease, but the underlying molecular mechanism remains to be defined. Here, we show that cyclophilin D, a mitochondrial matrix protein, in the PT causes kidney fibrogenesis in obstructive nephropathy. Our data suggest that targeting PT cyclophilin D could be beneficial to prevent fibrosis progression.


Assuntos
Ciclofilina D/metabolismo , Fibrose/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Regulação da Expressão Gênica , Nefropatias/etiologia , Ligadura , Masculino , Camundongos , Camundongos Knockout
20.
ACS Nano ; 15(9): 14744-14755, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34405985

RESUMO

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract cancer, and there is a lack of effective treatment. Here, we developed a nanoparticle platform (8P4 NP) that can deliver THZ1, a cyclin-dependent kinase 7 (CDK7) inhibitor, to treat GBC. Analysis of datasets demonstrated that CDK7 was positively correlated with poor prognosis. CDK7 inhibition suppressed cell proliferation, induced apoptosis, and caused cell cycle block in GBC cells. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II (RNAPII), resulting in a significant downregulation of transcriptional programs, with a preferential repression of oncogenic transcription factors. To improve the tumor targeting efficiency of THZ1, 8P4 NPs were prepared and assembled with THZ1 to form THZ1@8P4 NPs. Compared with free THZ1, THZ1@8P4 NPs showed more advantages in prolonging blood circulation, escaping from lysosomes and increasing cellular uptake. Importantly, THZ1@8P4 NPs demonstrated a more significant inhibition effect on GBC cells than free THZ1 in vitro. In addition, THZ1@8P4 NPs could efficiently deliver THZ1 to tumor sites in a patient-derived xenograft model of early recurrence, leading to tumor regression and transcriptional inhibition with minimal toxicity. In summary, we conclude that THZ1@8P4 NPs provide a potent therapeutic strategy that targets CDK7-mediated transcriptional addiction in GBC.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias da Vesícula Biliar , Nanopartículas , Fenilenodiaminas/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Sistemas de Liberação de Medicamentos , Neoplasias da Vesícula Biliar/terapia , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto
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