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1.
PLoS One ; 15(6): e0234708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555680

RESUMO

Fibroblast growth factor receptors (FGFRs) are frequently altered in a variety of human cancer cells and are overexpressed in hepatocellular carcinoma (HCC). Several literatures have proven that they are efficacious for HCC therapy, however, the underlying mechanism remains unclear. Here, we found FGFR4 was overexpressed in HCC cell lines HepG2 and Hep3B and we used PD173074, an FGFR4 inhibitor, to explore the role of FGFR4 and its underlying mechanism in these cell lines. The results showed that PD173074 significantly arrested HepG2 and Hep3B cells in G1 phase and inhibited cell proliferation. Furthermore, Western blot analysis revealed that PD173074 decreased the levels of P-FRS2α, P-ERK, CDK2, cyclin E and NF-κB (p65) in the nucleus while it increased the levels of ubiquitin and CUL3, an E3 ubiquitin ligase which involves in cyclin E degradation. Meanwhile, the data from RT-qPCR showed that PD173074 also decreased miR-141 level. In conclusion, these results suggest that FGFR4 is involved in HCC by ERK/CUL3/cyclin E signaling pathway, and the finding may provide a potential theoretical basis for treatment by targeting FGFR4 in HCC.


Assuntos
Proteínas Culina/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pirimidinas/farmacologia , Ubiquitina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Culina/antagonistas & inibidores , Proteínas Culina/genética , Ciclina E/metabolismo , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
2.
Anticancer Res ; 40(6): 3209-3220, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487615

RESUMO

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is one among the most common cancers worldwide. Recently, dietary phytochemicals have been reported as an attractive approach to improve the symptoms of NSCLC patients. Tannic acid is a natural polyphenol, which is known to have anticancer effects on in vitro models of breast, gingival and colon cancer. However, the molecular mechanisms associated with the actions of tannic acid on A549 human lung cancer cells have not been elucidated. MATERIALS AND METHODS: In this study, we analyzed the effect of tannic acid on A549 cells and their underlying mechanisms using western blotting, flow cytometry, invasion assay and tumorsphere formation assay. RESULTS: Tannic acid treatment suppressed the viability of A549 cells through cell cycle arrest and induction of the intrinsic pathways of apoptosis. In addition, the various malignant phenotypes of A549 cells including invasion, migration, and stemness were inhibited by tannic acid treatment. CONCLUSION: Tannic acid could be used as an effective inhibitor of lung cancer progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Taninos/uso terapêutico , Células A549 , Apoptose , Linhagem Celular Tumoral , Humanos , Transdução de Sinais , Taninos/farmacologia
3.
Chem Biol Interact ; 324: 109087, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32294457

RESUMO

Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1-4, triaryl bis-guanidine 5 and bis-N-substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro, in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC50 values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 µM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G0/G1 cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , DNA/metabolismo , Guanidinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Guanidinas/química , Guanidinas/metabolismo , Humanos , Fígado/patologia , Camundongos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
4.
Int J Nanomedicine ; 15: 1997-2010, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273698

RESUMO

Background: As one of the most widely produced engineered nanomaterials, titanium dioxide nanoparticles (nano-TiO2) are used in biomedicine and healthcare products, and as implant scaffolds; therefore, the toxic mechanism of nano-TiO2 has been extensively investigated with a view to guiding application. Three-dimensional (3D) spheroid models can simplify the complex physiological environment and mimic the in vivo architecture of tissues, which is optimal for the assessment of nano-TiO2 toxicity under ultraviolet A (UVA) irradiation. Methods and Results: In the present study, the toxicity of nano-TiO2 under UVA irradiation was investigated in 3D H22 spheroids cultured in fibrin gels. A significant reduction of approximately 25% in spheroid diameter was observed following treatment with 100 µg/mL nano-TiO2 under UVA irradiation after seven days of culture. Nano-TiO2 under UVA irradiation triggered the initiation of the TGF-ß/Smad signaling pathway, increasing the expression levels of TGF-ß1, Smad3, Cdkn1a, and Cdkn2b at both the mRNA and protein level, which resulted in cell cycle arrest in the G1 phase. In addition, nano-TiO2 under UVA irradiation also triggered the production of reactive oxygen species (ROS), which were shown to be involved in cell cycle regulation and the induction of TGF-ß1 expression. Conclusion: Nano-TiO2 under UVA irradiation induced cell cycle arrest in the G1 phase and the formation of smaller spheroids, which were associated with TGF-ß/Smad signaling pathway activation and ROS generation. These results reveal the toxic mechanism of nano-TiO2 under UVA irradiation, providing the possibility for 3D spheroid models to be used in nanotoxicology studies.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Titânio/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Camundongos , Nanopartículas/química , Proteína Smad3/genética , Proteína Smad3/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/efeitos da radiação , Raios Ultravioleta
5.
Anticancer Res ; 40(3): 1315-1323, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132028

RESUMO

BACKGROUND/AIM: Temozolomide (TMZ) induces prolonged arrest of human glioma cells in the G2/M phase and inhibition of the G2 checkpoint intensifies the effect of TMZ. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. MATERIALS AND METHODS: To clarify the mechanism of TMZ resistance, we established TMZ-resistant (TR) clones by serial treatment of U87MG cells with TMZ. We evaluated TMZ-induced cell cycle arrest and the effect of various G2 checkpoint inhibitors. RESULTS: We observed that longer exposure (over 6 months) to TMZ enriched the proportion of TR clones that underwent only minimal G2 arrest following TMZ treatment compared to short exposure (4 months) to TMZ. Expression of MSH6 was reduced in these clones. None of the G2 checkpoint inhibitors could resensitize TR clones to TMZ. CONCLUSION: Longer drug treatment may induce resistance of cells to DNA damaging agent(s) by means of mismatch repair modification.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Reparo de Erro de Pareamento de DNA , Glioblastoma/tratamento farmacológico , Temozolomida/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/patologia , Humanos
6.
Phytomedicine ; 69: 153183, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32113150

RESUMO

BACKGROUND: Osteosarcoma (OS) is a significant threat to the lives of children and young adults. Although neoadjuvant chemotherapy is the first choice of treatment for OS, it is limited by serious side-effects and cancer metastasis. ß-Elemonic acid (ß-EA), an active component extracted from Boswellia carterii Birdw., has been reported to exhibit potential anti-inflammatory and anticancer activities. However, the anti-tumor effects and underlying mechanisms on OS as well as pharmacokinetic characteristics of ß-EA remain unknown. PURPOSE: This study was aimed to investigating the anti-tumor effects of ß-EA on human OS, the underlying mechanisms, and the pharmacokinetic and tissue distribution characteristics. STUDY DESIGN AND METHODS: Cell viability and colony formation assays were performed to determine the effect of ß-EA cell on cell proliferation. Apoptosis rates, mitochondrial membrane potential and cell cycle features were analyzed by flow cytometry. qRT-PCR, Western blot, immunofluorescence and immunohistochemical assays were conducted to evaluate the expression levels of genes or proteins related to the pathways affected by ß-EA in vitro and in vivo. Cell migration and invasion were evaluated in wound healing and Transwell chamber assays. The effects and pharmacokinetic characteristics of ß-EA in vivo were evaluated by analyzing tumor suppression, pharmacokinetics and tissue distribution. RESULTS: Explorations indicated that endoplasmic reticulum (ER) stress conditions provoked by ß-EA activated the PERK/eIF2α/ATF4 branch of the unfolded protein reaction (UPR), stimulating C/EBP homologous protein (CHOP)-regulated apoptosis and inducing Ca2+ leakage leading to caspase-dependent apoptosis. Furthermore, ß-EA induced G0/G1 cell cycle arrest and inhibited metastasis of HOS and 143B cells by attenuating Wnt/ß-catenin signaling effects, which included decreased levels of p-Akt(Ser473), p-Gsk3ß (Ser9), Wnt/ß-catenin target genes (c-Myc and CyclinD1) along with a decline in nuclear ß-catenin accumulation. The fast absorption, short elimination half-life, and linear pharmacokinetic characteristics of ß-EA were also revealed. The distribution of ß-EA was detected in the tumor and bone tissues. CONCLUSIONS: Overall, both in vitro and in vivo investigations showed the potential of ß-EA for the treatment of human OS. The pharmacokinetic profile and considerable distribution in the tumor and bone tissues warrant further preclinical or even clinical studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Fenantrenos/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Distribuição Tecidual , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo , eIF-2 Quinase/metabolismo
7.
Arch Med Res ; 51(3): 233-244, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32139108

RESUMO

OBJECTIVE: To evaluate the anti-cancer effect of unmethylated cytosine-phosphorothioate-guanine (CpG)-containing oligodeoxynucleotides (ODNs) on human bladder cancer UM-UC-3 cells, our study was carried out. METHODS: The viability of cells (UM-UC-3, T24 and SV-HUC-1) with CpG ODN treatments was examined by cell counting kit-8 (CCK-8) assay. Apoptosis and cell cycle phase were determined by flow cytometry analysis. Pre-apoptosis factors of caspase-3, p53, B-cell lymphoma 2 associated X protein (Bax) and anti-apoptosis factor of B-cell lymphoma 2 (Bcl-2) were detected by western blot. RESULTS: Experimental results showed that the viability of human bladder cancer cells (UM-UC-3 and T24) with CpG ODN treatment was decreased and the viability of human normal urothelial cells (SV-HUC-1) with CpG ODN treatment was increased with time-dependance manner. Moreover, CpG ODN increased the apoptosis rate of UM-UC-3 cells and arrested more cells in G0G1 phase. Furthermore, the expression of caspase-3, p53 and Bax were increased and the expression of Bcl-2 was decreased with CpG ODN treatment on UM-UC-3 cells. CONCLUSION: CpG ODN promoted the proliferation of normal urinary transitional epithelial cells (SV-HUC-1) and inhibited the cell viability of human bladder cancer cells (UM-UC-3 and T24) in vitro. CpG ODN induced the apoptosis of human bladder cancer (UM-UC-3) cells in a cascade progress via enhancing the expression of caspase-3, p53 and Bax, and inhibiting the expression of Bcl-2 with significant time-dependancy. CpG ODN inhibited cell cycle distribution of human bladder cancer (UM-UC-3) cells with more cells were arrested in G0G1 phase. This study suggested that the CpG ODN is the potential candidate on human bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citosina/farmacologia , Células Epiteliais/fisiologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Guanina/farmacologia , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteína X Associada a bcl-2/metabolismo
8.
Chemosphere ; 248: 126026, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32006839

RESUMO

Phosphorus-containing flame retardants (PFRs) have been frequently detected in various environmental samples at relatively high concentrations and are considered emerging environmental pollutants. However, their biological effects and the underlying mechanism remain unclear, especially alkyl-PFRs. In this study, a battery of in vitro bioassays was conducted to analyze the cytotoxicity, oxidative stress, mitochondrial impairment, DNA damage and the involved molecular mechanisms of several selected alkyl-PFRs. Results showed that alkyl-PFRs induced structural related toxicity, where alkyl-PFRs with higher logKow values induced higher cytotoxicity. Long-chain alkyl-PFRs caused mitochondrial and DNA damage, resulting from intracellular reactive oxygen species (ROS) and mitochondrial superoxide overproduction; while short-chain alkyl-PFRs displayed adverse outcomes by significantly impairing mitochondria without obvious ROS generation. In addition, alkyl-PFRs caused DNA damage-induced cell cycle arrest, as determined by flow cytometry, and transcriptionally upregulated key transcription factors in p53/p21-mediated cell cycle pathways. Moreover, compared to the control condition, triisobutyl phosphate and trimethyl phosphate exposure increased the sub-G1 apoptotic peak and upregulated the p53/bax apoptosis pathway, indicating potential cell apoptosis at the cellular and molecular levels. These results provide insight into PFR toxicity and the involved mode of action and indicate the mitochondria is an important target for some alkyl-PFRs.


Assuntos
Retardadores de Chama/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Dano ao DNA , Poluentes Ambientais/toxicidade , Humanos , Mitocôndrias/efeitos dos fármacos , Organofosfatos/toxicidade , Fósforo/química , Testes de Toxicidade , Fatores de Transcrição/genética
9.
Phytother Res ; 34(7): 1619-1628, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32072698

RESUMO

Matrine (MAT) is an alkaloid in the dried roots of Sophora flavescens. The antitumor activity has been testified in colon cancer. Howbeit, the latent mechanism is still indistinct. The research probed the antitumor mechanism of MAT in colon cancer cells. MAT (0.25, 0.5, 0.75, 1, and 1.25 mM) was utilized to stimulate SW480 and SW620 cells for 24, 48, and 72 hr. Cell viability, apoptosis, cell cycle, and the correlative proteins were assessed via Cell Counting Kit-8, flow cytometry, and Western blot. microRNA-22 (miR-22) in MAT-treated or miR-22-silenced cells was estimated via real-time quantitative polymerase chain reaction. The functions of miR-22 inhibition were reassessed. Western blot was conducted for quantifying ß-catenin, MEK, and ERK. Luciferase reporter assay was done for confirming the targeting relationship between miR-22 and ERBB3 or MECOM. MAT prohibited cell viability, accelerated apoptosis, and triggered cells cycle stagnation at G0/G1 phase. Additionally, miR-22 was elevated by MAT; meanwhile, the influences of MAT were all inverted by miR-22 inhibitor. MAT enhanced the expression of miR-22, thereby obstructing Wnt/ß-catenin and MEK/ERK pathways. miR-22 had a potential to target mRNA 3'UTR of ERBB3 and MECOM. These discoveries manifested that MAT could evoke colon cancer cell apoptosis and G0/G1 cell cycle arrest via elevating miR-22.


Assuntos
Alcaloides/efeitos adversos , Anti-Helmínticos/efeitos adversos , Neoplasias do Colo/induzido quimicamente , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , MicroRNAs/metabolismo , Quinolizinas/efeitos adversos , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Transfecção
10.
J Med Chem ; 63(3): 1281-1297, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935086

RESUMO

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 µM) and cellular inhibitory activity (IC50 = 1.73 µM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperoninas/química , Chaperoninas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
11.
J Med Chem ; 63(3): 1199-1215, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935092

RESUMO

In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL2+ stability constant values in solution, strongly supports their cytotoxicity. These data along with quantum mechanical studies have enabled to establish a precise structure-activity relationship. Moreover, L1a and L5a showed appropriate drug-likeness by in silico methods. Based on these promising results, L1a and L5a should be considered a new class of zinc-chelating anticancer agents that deserves further development.


Assuntos
Antineoplásicos/farmacologia , Quelantes/farmacologia , Poliaminas/farmacologia , Zinco/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/farmacocinética , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Poliaminas/síntese química , Poliaminas/farmacocinética , Teoria Quântica , Relação Estrutura-Atividade , Zinco/química
12.
Eur J Med Chem ; 189: 112061, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951960

RESUMO

Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.


Assuntos
Antineoplásicos/farmacologia , Proteólise/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Piridinas/síntese química , Pirimidinas/síntese química
13.
J Photochem Photobiol B ; 202: 111666, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837585

RESUMO

In this study, the effect of Polyp-Au-GO nanocomposite on VSMC proliferation, cell cycle proteins, down-regulation of mRNA in the rat was tested. Briefly, Polyp-Au-GO composite material was synthesized and characterized by UV-Vis spectra, X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). Polyp-Au-GO composite exhibited the absorbance peak at 530 nm. XRD analysis confirmed the crystalline particle with size ranging between 16.5 and 32.6 nm. The crystallinity differences of the nanocomposite were examined by Raman spectroscopy analysis. The presence of a strong band (1500 cm-1) and the absence of other lower frequency bands confirmed that the absence of crystallinity of Polyp-Au-GO nanocomposite. The thermal properties of Polyp-Au-GO nanocomposite were determined by TGA analysis. The results revealed that 15% of its weight loss has occurred at 300 °C. Further, the growth of VSMCs was inhibited by the treatment of Polyp-Au-GO composite at 72 h. The IC50 value was registered at 0.57 µg/mL. Additionally, the Polyp-Au-GO composite arrest G1 cell cycle and down-regulated cell cycle proteins. These Polyp-Au-GO composite also reduced the extracellular ERK1/2 phosphorylation. Furthermore, Polyp-Au-GO composite inhibited TNF-R-evoked inflammatory responses. Moreover, Polyp-Au-GO composite inhibited of CEC proliferation. These results suggest that Polyp-Au-GO composite inhibits VSMC proliferation and TNF-R-mediated inflammatory responses. This study suggested the therapeutic role of Polyp-Au-GO composite in cardiovascular disease.


Assuntos
Grafite/química , Nanocompostos/química , Polifenóis/química , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Nanocompostos/toxicidade , Tamanho da Partícula , Fosforilação/efeitos dos fármacos , Polifenóis/farmacologia , Ratos
14.
Ecotoxicol Environ Saf ; 187: 109851, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670181

RESUMO

Cadmium is a heavy metal pollutant that has been reported to cause oxidative stress, apoptosis, and autophagy in cells, while the flavone isoorientin is a traditional Chinese medicine extract that has proven antioxidant and anti-inflammatory properties. Accordingly, in this study we used the rat proximal tubular cell line NRK-52E and primary rat proximal tubular (rPT) cells as models to investigate the effects of isoorientin against Cadmium-induced cell injury and the mechanism of these effects. Comet assay, Western blot, flow cytometry, immunofluorescence, and transmission electron microscopy were used to evaluate cell damage and cell-cycle-related protein expression. Furthermore, real-time cell analysis, cell-counting kit-8, and ELISA were used to investigate the role of isoorientin in Cadmium-induced cell injury. The results revealed that treatment of rat renal tubular epithelial cells with 2.5 µM Cd for 12 h resulted in DNA damage and G0/G1 cell cycle arrest, while isoorientin attenuated this Cd-induced damage.


Assuntos
Antioxidantes/farmacologia , Cádmio/toxicidade , Dano ao DNA/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Luteolina/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
15.
Biosci Biotechnol Biochem ; 84(1): 63-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31462179

RESUMO

A natural isoquinoline alkaloid, berberine, has been known to exhibit anti-tumor activity in various cancer cells via inducing cell cycle arrest. However, it has not been investigated whether berberine and its analogs inhibit the growth of rhabdomyosarcoma (RMS), which is the most frequent soft tissue tumor in children. The present study examined the anti-tumor effects of berberine and palmatine on expansions of three human embryonal RMS cell lines; ERMS1, KYM1, and RD. Intracellular incorporation of berberine was relatively higher than that of palmatine in every RMS cell line. Berberine significantly inhibited the cell cycle of all RMS cells at G1 phase. On the other hand, palmatine only suppressed the growth of RD cells. Both of berberine and palmatine strongly inhibited the growth of tumorsphere of RD cells in three-dimensional culture. These results indicate that berberine derivatives have the potential of anti-tumor drugs for RMS therapy.Abbreviations: ARMS: alveolar rhabdomyosarcoma; ERMS: embryonal rhabdomyosarcoma; RMS: rhabdomyosarcoma.


Assuntos
Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Berberina/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Antineoplásicos/química , Berberina/análogos & derivados , Berberina/química , Alcaloides de Berberina/química , Linhagem Celular Tumoral , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/genética , Conformação Molecular , Simulação de Acoplamento Molecular , Phellodendron/química , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Embrionário/metabolismo
16.
Artif Cells Nanomed Biotechnol ; 48(1): 8-14, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852248

RESUMO

Osteoarthritis is a common type of degenerative joint disease. Inflammation-related chondrocyte senescence plays a major role in the pathogenesis of osteoarthritis. Omentin-1 is a newly identified anti-inflammatory adipokine involved in lipid metabolism. In this study, we examined the biological function of omentin-1 in cultured chondrocytes. The presence of omentin-1 potently suppresses IL-1ß-induced cellular senescence as revealed by staining with senescence-associated beta-galactosidase (SA-ß-Gal). At the cellular level, omentin-1 attenuates IL-1ß-induced G1 phase cell-cycle arrest. Mechanistically, we demonstrate that omentin-1 reduced IL-1ß-induced expression of senescent factors including caveolin-1, p21, and PAI-1 as well as p53 acetylation through ameliorating SIRT1 reduction. Notably, silencing of SIRT1 abolishes IL-1ß-induced senescence along with the induction of p21 and PAI-1, suggesting that the action of omentin-1 in chondrocytes is dependent on SIRT1. Collectively, our results revealed the molecular mechanism through which the adipokine omentin-1 exerts a beneficial effect, thereby protecting chondrocytes from senescence. Thus, omentin-1 could have clinical implication in the treatment of osteoarthritis.


Assuntos
Adipocinas/farmacologia , Senescência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Interleucina-1beta/farmacologia , Caveolina 1/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Citoproteção/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Inibidor 1 de Ativador de Plasminogênio/genética , Sirtuína 1/metabolismo , Ativação Transcricional/efeitos dos fármacos
17.
J Agric Food Chem ; 68(1): 213-224, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31861958

RESUMO

Asparanin A (AA), a steroidal saponin from Asparagus officinalis L., has anticancer activity: however, its detailed molecular mechanisms in endometrial cancer (EC) have not been studied so far. We evaluated the anticancer activity and underlying mechanism of AA on EC cell line Ishikawa in vitro and in vivo. AA inhibited the Ishikawa cell proliferation and caused cell morphology alteration and cell cycle arrest in G0/G1 phase. Moreover, it could induce apoptosis through mitochondrial pathway, including the deregulation of Bak/Bcl-xl ratio which led to the generation of ROS, up-regulation of cytochrome c followed by decrease of Δψm, and activation of caspases, besides inhibition of the PI3K/AKT/mTOR pathway. In vivo data showed that administration of AA significantly inhibited the tumor tissue cell proliferation, reduced the tumor growth, and induced the apoptosis occurrence. AA can be a possible functional food ingredient to cure endometrial cancer followed by clinical trials.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Asparagus (Planta)/química , Neoplasias do Endométrio/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Neoplasias do Endométrio/fisiopatologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
PLoS One ; 14(12): e0226068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825988

RESUMO

Every year, more than 250,000 invasive candidiasis infections are reported with 50,000 deaths worldwide. The limited number of antifungal agents necessitates the need for alternative antifungals with potential novel targets. The 2-benzylidenebenzofuran-3-(2H)-ones have become an attractive scaffold for antifungal drug design. This study aimed to determine the antifungal activity of a synthetic aurone compound and characterize its mode of action. Using the broth microdilution method, aurone SH1009 exhibited inhibition against C. albicans, including resistant isolates, as well as C. glabrata, and C. tropicalis with IC50 values of 4-29 µM. Cytotoxicity assays using human THP-1, HepG2, and A549 human cell lines showed selective toxicity toward fungal cells. The mode of action for SH1009 was characterized using chemical-genetic interaction via haploinsufficiency (HIP) and homozygous (HOP) profiling of a uniquely barcoded Saccharomyces cerevisiae mutant collection. Approximately 5300 mutants were competitively treated with SH1009 followed by DNA extraction, amplification of unique barcodes, and quantification of each mutant using multiplexed next-generation sequencing. Barcode post-sequencing analysis revealed 238 sensitive and resistant mutants that significantly (FDR P values ≤ 0.05) responded to aurone SH1009. The enrichment analysis of KEGG pathways and gene ontology demonstrated the cell cycle pathway as the most significantly enriched pathway along with DNA replication, cell division, actin cytoskeleton organization, and endocytosis. Phenotypic studies of these significantly enriched responses were validated in C. albicans. Flow cytometric analysis of SH1009-treated C. albicans revealed a significant accumulation of cells in G1 phase, indicating cell cycle arrest. Fluorescence microscopy detected abnormally interrupted actin dynamics, resulting in enlarged, unbudded cells. RT-qPCR confirmed the effects of SH1009 in differentially expressed cell cycle, actin polymerization, and signal transduction genes. These findings indicate the target of SH1009 as a cell cycle-dependent organization of the actin cytoskeleton, suggesting a novel mode of action of the aurone compound as an antifungal inhibitor.


Assuntos
Antifúngicos/farmacologia , Benzofuranos/farmacologia , Candida albicans/efeitos dos fármacos , Citoesqueleto de Actina/efeitos dos fármacos , Antifúngicos/química , Benzofuranos/química , Candida albicans/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Farmacorresistência Fúngica/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Ontologia Genética , Humanos , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
19.
Artif Cells Nanomed Biotechnol ; 47(1): 4131-4138, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701766

RESUMO

Background: Accumulating evidence displays that sinomenine hydrochloride (SH) are utilised to treat a variety of cancers. Nevertheless, the influences of SH on ovarian cancer stay blurry. We endeavoured to uncover the antitumor effects of SH on ovarian cancer and underlying mechanism(s).Methods: Human ovarian epithelial cell line (HOEpiC), Caov3 and SKOV3 cells were administrated with SH and/or transfection with pc-long non-coding RNA (lncRNA) human ovarian cancer-specific transcript 2 (HOST2), then cell viability, cell cycle and apoptosis and the related-proteins were respectively inspected by MTT, flow cytometry, and Western blot. In addition, expression of HOST2 was investigated by real-time PCR. Kaplan-Meier manner with the log-rank investigation was achieved to calculate overall survival.Results: SH remarkably repressed cell viability, evoked apoptosis and induced cell cycle arrest in G0/G1. Moreover, SH statistically decreased HOST2 expression in Caov3 and SKOV3 cells. Overexpression of HOST2 significantly reversed the effects of SH on Caov3 cell viability, cell cycle and apoptosis. Clinical findings confirmed that HOST2 was profoundly higher expressed in ovarian cancer tissues and cells, and HOST2 predicated unfavourable prognosis of ovarian cancer individuals.Conclusion: Our findings recommended that SH exerted the antitumor effect in ovarian cancer cells by hindering expression of HOST2.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Morfinanos/farmacologia , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Prognóstico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética
20.
J BUON ; 24(4): 1686-1691, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31646826

RESUMO

PURPOSE: Esculetin is an important bioactive coumarin with amazing potential to suppress the growth of cancer cells. The present study was designed to investigate the anticancer effects of esculetin against the human leukemia HL-60 cells. METHODS: CCK-8 assay was used to assess cell viability. DAPI and annexin V/propidium iodide (PI) staining was performed to investigate the induction of apoptosis. Autophagy was detected by electron microscopic analysis. Flow cytometry was used for cell cycle analysis and Western blotting was used to estimate protein expression. RESULTS: Esculetin suppressed the proliferation of HL-60 cells dose-dependently. The IC50 of esculetin against HL-60 cells was observed to be 20 µM. The anticancer effects of esculetin against HL-60 cells occurred though different mechanisms. Esculetin induced apoptosis and autophagy in leukemia cells, which were accompanied by alteration in the expression of apoptosis as well as autophagy-related proteins. Esculetin also triggered G0/G1 cell cycle arrest in HL-60 cells, which was also accompanied by suppression of Cyclin D1 and D3. Esculetin could also block the Raf/MEK/ERK signalling pathway in leukemia cells in a concentration-dependent manner. CONCLUSION: These results indicate that esculetin inhibits the growth of leukemia cells and hence may prove beneficial for treating leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Leucemia/tratamento farmacológico , Umbeliferonas/farmacologia , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia/genética , Leucemia/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases raf/genética
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