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1.
Anticancer Res ; 40(1): 9-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892549

RESUMO

BACKGROUND/AIM: Inhibition of apoptosis is one of the hallmarks of cancer, and anti-apoptotic genes are often targets of genetic and epigenetic alterations. Cellular inhibitor of apoptosis 2 (cIAP2) has a role in degrading caspases by linking them to ubiquitin molecules, and is upregulated in triple-negative breast cancer (TNBC). Previous studies have demonstrated that cIAP2 may play a role in the epithelial-to-mesenchymal transition (EMT). MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was administered to triple-negative breast cancer (TNBC) cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. RESULTS: The compounds were able to decrease the expression of cIAP2 while increasing the expression of pro-apoptotic caspase 7. There were also changes in histone modifications, suggesting a role of epigenetic mechanisms in these changes in expression of cIAP2. These changes resulted in an increase in apoptosis. SAHA and EGCG were also capable of limiting TNBC cell migration across a fibronectin (FN) matrix. CONCLUSION: SAHA and EGCG reduce the metastatic potential of TNBC by inducing the apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/genética , Catequina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Vorinostat/farmacologia , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Catequina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Anticancer Res ; 40(1): 53-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892552

RESUMO

BACKGROUND/AIM: Medulloblastoma (MB) accounts for ~20% of pediatric malignant central nervous system tumors. Treatment strategies, including surgery, radiation therapy and/or chemotherapy, are effective, but recurrence and metastasis frequently occur. Therefore, novel therapies are required. Herein, the effects of fibroblast growth factor receptor (FGFR) and phosphoinositide 3-kinase (PI3K) inhibitors on MB cells lines were evaluated. MATERIALS AND METHODS: MB cell lines (UW228-3, DAOY, Med8a, D425, D283) were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BYL719) inhibitors by viability, cytotoxicity, apoptosis, and proliferation assays. RESULTS: Single treatments with FGFR and PI3K inhibitors decreased viability and proliferation in a dose-dependent pattern in most cell lines. Combinination of the two type of drugs, increased sensitivity, especially of the most resistant cell line UW228-3. CONCLUSION: Combination treatments with FGFR and PI3K inhibitors were superior to single treatments with FGFR and PI3K inhibitors, especially with BEZ235, for MB cell lines.


Assuntos
Meduloblastoma/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Meduloblastoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553

RESUMO

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
4.
Anticancer Res ; 40(1): 109-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892559

RESUMO

BACKGROUND/AIM: Although molecular targeting therapy is an attractive treatment for cancer, resistance eventually develops in most cases. Here, we evaluated chemotherapeutic efficacy on non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor inhibitors mechanistically. MATERIALS AND METHODS: Antitumor effects of taxotere were evaluated using multiple models, including xenograft, and patient-derived models developed from adenocarcinoma cancer patients. Protein expressions were analyzed after drug treatment. RESULTS: Taxotere inhibited tumor growth of NSCLC cells harboring drug resistance, and reduced the expression of phosphorylated MET proto-oncogene, receptor tyrosine kinase (MET). A tumor-inhibitory effect of taxotere was also demonstrated in vivo in xenografts in mice, patient-derived primary lung tumor cells and patient-derived xenograft with concomitant repression of phosphorylated MET expression. Chemotherapeutic and MET-targeting drug exhibited a synergistic cell growth-inhibitory effect. CONCLUSION: These results suggest that the anticancer drug taxane may be an adjuvant for lung tumors exhibiting enhanced signaling of MET networks.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 40(1): 153-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892563

RESUMO

BACKGROUND/AIM: In this study, we evaluated the effect of galloflavin, an inhibitor of lactate dehydrogenase, in combination with metformin, an anti-diabetic drug and inhibitor of oxidative phosphorylation, on pancreatic ductal adenocarcinoma cells. MATERIALS AND METHODS: We explored the effect of galloflavin and metformin on proliferation and cell death of murine 6606PDA and human MIA PaCa-2 cells. RESULTS: We observed that monotherapies of galloflavin and metformin both inhibit proliferation and induce cancer cell death. Moreover, the combination of both agents increased these effects on pancreatic ductal adenocarcinoma cells. The inhibition of proliferation by this combination therapy can be detected under hypoxic and normoxic conditions, leading to the assumption that this therapy might impair insufficiently supplied solid tumors as well as small clusters of cancer cells, e.g. after metastatic dissemination. CONCLUSION: Galloflavin, especially in combination with metformin, has a strong anti-cancerous effect on pancreatic ductal adenocarcinoma cells.


Assuntos
Antineoplásicos/farmacologia , Isocumarinas/farmacologia , Metformina/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/farmacologia , Ácido Láctico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo
7.
Chem Pharm Bull (Tokyo) ; 68(1): 1-33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902899

RESUMO

Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates, in which the following items are covered. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation under neutral condition from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel ß-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.


Assuntos
Produtos Biológicos/química , Metais/química , Animais , Produtos Biológicos/síntese química , Proliferação de Células/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/química , Metano/metabolismo , Nitrilos/química , Nucleosídeos/síntese química , Nucleosídeos/química
8.
Chem Pharm Bull (Tokyo) ; 68(1): 77-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902903

RESUMO

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Piridonas/química , Proteínas Quinases Ativadas por AMP/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Piridonas/síntese química , Piridonas/farmacologia , Solubilidade , Relação Estrutura-Atividade
9.
Cancer Sci ; 111(1): 112-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675763

RESUMO

Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Fluvastatina/farmacologia , Neoplasias Renais/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
10.
Chem Pharm Bull (Tokyo) ; 68(1): 58-63, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31685780

RESUMO

Polycomb repressive complex 2 (PRC2) is an attractive drug target for anti-cancer treatment. Among the three core subunits (EZH2, EED and SUZ12) of PRC2, EZH2 is the catalytic subunit that methylates histone H3 lysine 27 (H3K27), while EED is the regulatory subunit. Besides the small-molecule inhibitors of EZH2, those targeting the protein-protein interaction (PPI) between EZH2 and EED have also been reported. Here, for the first time, we have identified the key residues that contributed most to the EED-EZH2 binding affinity by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations based on the 200 ns molecular dynamics simulation. Moreover, we report the identification of two novel and potent small-molecule inhibitors (35 and 49) of EZH2-EED interaction (bottom interaction surface) by virtual screening and biological evaluations. Binding modes of the two identified molecules with EED were probed by molecular docking. Additionally, 35 and 49 displayed cellular antiproliferative activity against diffuse large B-cell lymphoma (DLBCL) cancer cell line Toledo whose cell growth was driven by aberrant PRC2 activity. Our findings have provided structural insights for the design of novel EZH2-EED interaction inhibitors to regulate the activity of PRC2 complex.


Assuntos
Simulação de Acoplamento Molecular , Complexo Repressor Polycomb 2/metabolismo , Bibliotecas de Moléculas Pequenas/química , Sítios de Ligação , Ligação Competitiva , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Humanos , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/genética , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
11.
Cancer Sci ; 111(1): 47-58, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710162

RESUMO

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine-resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Quimiocina CCL2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Macrófagos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Intervalo Livre de Progressão , Receptores de Superfície Celular/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Tamoxifeno/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
12.
J Photochem Photobiol B ; 202: 111676, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837583

RESUMO

Wounds origins serious complications of lives of human beings which may leads to death. The important issue for the problem is infection during wound care management which delays wound healing process. These kinds of infections may be caused by the overuse or misuse of antibiotics, antidotes, usage of new drugs, not properly sterilized surgical instruments, not appropriate for pH level and imperfect wound dressing etc. during or after surgery. Hence in this report, antimicrobial action of pH responsive TA/KA composited hydrogel crosslinked with GO-QDs (TA/KA-GOQDs) using citric acid as cross-linker has been reported by demonstrating in-vitro and in-vivo studies for wound care management. The prepared samples of GOQDs, TA/KA hydrogel and TA/KA-GOQDs were characterized using FT-IR, XRD, SEM and TEM techniques. pH responsive hydrogel property of TA/KA was evaluated by swelling studies. In-vitro antibacterial studies was carried out by direct contact test method. Further, the prepared samples were tested in a wound healing model of rate with the wound of size 1.5 cm2 for in-vivo studies. After 16 days of treatment, the prepared samples for wound healing causes 100% wound areas closure. Histological observations were made by MT and HE staining process which proves keratinocytes proliferation by biocompatible and biocomposited TA/KA-GOQDs. The pH responsive TA/KA-GOQDs proved as efficient wound healing agent by faster keratinocytes proliferation within a compact period.


Assuntos
Materiais Biocompatíveis/farmacologia , Grafite/química , Hidrogéis/química , Queratinas/química , Pontos Quânticos/química , Cicatrização/efeitos dos fármacos , Animais , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Queratinócitos/citologia , Queratinócitos/metabolismo , Ratos , Pele/patologia , Staphylococcus aureus/efeitos dos fármacos
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.
Toxicol Lett ; 319: 22-30, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689473

RESUMO

Cadmium (Cd) has estrogen-like activities in breast cancer; it acts as a metalloestrogen in humans. Prospective cohort studies of Cd and breast cancer risk suggest a significant relationship between increased Cd intake and cancer incidence, with more pronounced effects for estrogen receptor α (ERα)-positive breast cancers. However, a recent systematic review with the highest level of evidence demonstrated no such relationship in post-menopausal women. Thus, the reported effects of Cd in pre- and post-menopausal ERα-positive breast cancers are inconsistent. MCF-7 human breast cancer cells normally exhibit growth through estradiol-triggered ERα signaling; however, the MCF-7 cells cultured in estrogen-deprived conditions for a long time (∼ 6 months) eventually result in LTED cells that can be used to utilize to study the proliferation of ERα-positive breast cancer cells obtained from post-menopausal women. Our results showed that unlike MCF-7 cells, LTED cells showed estradiol-independent growth because of constitutively activated ERα. Moreover, Cd (∼10 nM) stimulated ERα signaling in MCF-7 cells and ERα-expressing LTED cells, but not in LTED cells; in ERα-expressing LTED cells, this effect was reversed by ICI 182,780 (an ERα antagonist). Furthermore, in comparison with MCF-7 cells, the LTED cells expressed very low levels of G protein-coupled estrogen receptor 1 (GPER1), a membrane ER capable of stimulating the estrogenic activity of Cd. These findings suggest that the estrogenic action of Cd may be suppressed in LTED cells, and potentially in post-menopausal breast cancer.


Assuntos
Cloreto de Cádmio/toxicidade , Receptor alfa de Estrogênio/metabolismo , Estrogênios/biossíntese , Estrogênios/deficiência , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7
15.
Cancer Sci ; 111(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31692172

RESUMO

The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.


Assuntos
Aldeídos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Oxifedrina/farmacologia , Vasodilatadores/farmacologia , Aldeído Desidrogenase/metabolismo , Animais , Antioxidantes/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glutationa/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sulfassalazina/farmacologia
16.
J Photochem Photobiol B ; 202: 111652, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760374

RESUMO

The Biocompatibility and stability of nanoparticles using plants have been widely investigated due to its applications in the biomedical industry. Currently, there is a growing interest in nanoparticles in bone remodelling. Artemisia annua is an herbal plant commonly used in the treatment of various ailments. This study investigated the zinc oxide nanoparticles (ZnO NPs) using the green synthesis technique from A. annua and the effects of A. annua ZnO-NPs on osteoblast differentiation and inhibition of osteoclast formation. The formulated ZnO-NPs from A. annua were characterized by using various spectroscopic and microscopic methods Fourier transform-infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray diffraction (XRD), and UV-Visible spectroscopy. The disc diffusion method was adopted to test the antimicrobial efficacy of ZnO-NPs. The viability of MG-63 cells were assayed by MTT test and Osteogenic-related assays like Real-time PCR and Mineralization assay were adopted to determine the effects of A. annua ZnO-NPs on the multiplication and differentiation of human osteoblast-like MG-63 cells. The characterization of A. annua ZnO-NPs revealed the crystalline nature with high zinc content and the presence of bioactive compounds from A. annua extract. The synthesized A. annua ZnO-NPs indicate significant antimicrobial potential. Besides, A. annua ZnO-NPs enhanced the proliferation, differentiation, and mineralization without causing significant cytotoxic impact on MG-63 cells. These effects indicate that A. annua ZnO-NPs can both stimulate bone formation via the differentiation of MG-63 cells. Hence, it was concluded that A. annua ZnO-NPs can be a promising agent for the treatment of bone deformities and bone-related diseases, however further research also required to explore the clear mechanism of A. annua ZnO-NPs in the formation and differentiation of MG-63 cells.


Assuntos
Artemisia annua/química , Diferenciação Celular , Proliferação de Células , Nanopartículas Metálicas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Artemisia annua/metabolismo , Cálcio/metabolismo , Candida/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Química Verde , Humanos , Nanopartículas Metálicas/toxicidade , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Óxido de Zinco/química
17.
Ultrasonics ; 101: 106033, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31561207

RESUMO

The objective of this study was to use ultrasound in combination with nanoparticulate formulations of taxane drugs for an additive approach to overcome multidrug resistance (MDR). Polymeric nanoparticulate formulations containing both chemotherapeutic taxane drugs and a polymeric inhibitor (MePEG17-b-PCL5) of drug resistant proteins have been previously developed in an attempt to overcome MDR in cells. High frequency (>1 MHz) ultrasound has been shown to increase the uptake of cytotoxic drugs in MDR proliferating cells and has been suggested as a different way to overcome MDR, resensitize drug resistant cancer cells and allow for chemotherapeutic efficacy. MDCK-MDR cells were incubated with docetaxel (DTX) or paclitaxel (PTX) loaded, solid core, nanoparticles made from a 50:50 ratio of two diblock copolymers, MePEG114-b-PCL200 and MePEG17-b-PCL5 (PCL200/PCL5). The accumulation of drug in MDCK-MDR cells was measured using radiolabeled drug and the viability of cells was determined using an MTS cell proliferation assay. The effect of ultrasound (4 MHz, 32 W/cm2, 10 s, 25% duty cycle) on drug uptake and cell viability was studied. Using free DTX or PTX, MDCK-MDR cells were killed at sublethal doses of drug with the P-gp inhibitor (MePEG17-b-PCL5) present at a concentration of just 0.006% (m/v) and cell death began after just 3 h of incubation. Using sublethal incubation doses of PTX or DTX in PCL200/PCL5 nanoparticles for 90 min, followed by a second exposure to blank PCL200/PCL5 nanoparticles, cell viability dropped by approximately 60% at 24 h. Drug accumulation increased by 1.43-1.9 fold following five bursts of ultrasound applied at 90 min. Both, increased ultrasound exposure and increased concentrations of blank nanoparticles during the second incubation allowed for increased levels of cell death. The combined use of ultrasound with taxane and P-gp inhibitor loaded polymeric nanoparticles may allow for increased accumulation of drug and inhibitor which may then release both agents inside cells in a controlled manner to overcome drug resistance in MDR cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Docetaxel/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Polietilenoglicóis/farmacologia , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Cães , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Paclitaxel/química , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Células Tumorais Cultivadas
18.
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
19.
J Enzyme Inhib Med Chem ; 35(1): 72-84, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682465

RESUMO

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Desenho de Drogas , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
20.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

A series of naphthalene-chalcone derivatives (3a-3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
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