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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.
Gene ; 725: 144159, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31629818

RESUMO

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide due to its frequent metastasis, tumor recurrence, and lack of curative treatment. However, the underlying molecular mechanisms involved in HCC progression remain unclear. Here, we analyzed the global gene expression of spontaneous liver tumor tissue from CBA/CaJ mice by RNA-Seq and identified 10,706 and 10,374 genes in the normal and liver tumor groups, respectively. Only 9793 genes were expressed in both, 913 genes were identified in only the liver tumor group, and 581 genes were found in normal liver tissues. There were 2054 differentially expressed genes (DEGs), with 975 down-regulated genes and 1079 up-regulated genes. Gene ontology (GO) term enrichment analysis showed that 43 up-regulated genes were significantly associated with cell cycle regulation and hundreds of up-regulated genes were related to cell migration, adhesion, or metabolic processes. KEGG pathway enrichment also demonstrated that some DEGs were tightly associated with the cell cycle, extracellular matrix (ECM)-receptor interactions, as well as protein digestion and absorption pathways, indicating that the activation of these oncogenic cascades was closely related to tumor liver progression in CBA/CaJ mice. Ninety-three genes with elevated expression levels preferentially localized in microtubules, kinetochores, and spindles play an important role during mitosis and meiosis and are associated with the reorganization of the cytoskeleton in cancer cells during migration and invasion. Some ECM-related genes were significantly different in the tumor group, including collagen types I, III, IV, V, and VI, non-collagenous glycoproteins, laminin, and fibronectin. We further validated the functions of upregulated genes, such as cyclin-dependent kinase 1 (CDK1) and polo-like kinase 1 (PLK1), with regards to cell cycle regulation, apoptosis, and proliferation in normal human liver or liver tumor-derived cell lines. Our results indicated that the cell cycle dysregulation, ECM-receptor interaction, and cytoskeleton-associated genes in mouse livers may promote HCC progression and deciphering the function of the genes will help investigators understand the underlying molecular mechanism of HCC.


Assuntos
Neoplasias Hepáticas Experimentais/genética , Animais , Apoptose/genética , Proteína Quinase CDC2/metabolismo , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos CBA , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Transcrição Genética , Transcriptoma
3.
Biol Res ; 52(1): 57, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767027

RESUMO

BACKGROUND: Gastric cancer is a common malignant tumor with high morbidity and mortality worldwide, which seriously affects human health. Gramicidin is a short peptide antibiotic which could be used for treating infection induced by bacteria or fungi. However, the anti-cancer effect of gramicidin on gastric cancer cells and its underlying mechanism remains largely unknown. RESULTS: Gastric cancer cells SGC-7901, BGC-823 and normal gastric mucosal cells GES-1 were treated with different concentrations of gramicidin respectively. The results of CCK-8 experiment revealed cellular toxicity of gramicidin to cancer cells while cell colony formation assay showed that gramicidin significantly inhibited the proliferation of gastric cancer cells, but had little effect on normal gastric mucosal cells. In addition, the wound healing assay showed that gramicidin inhibited the migration of SGC-7901 cell. Meanwhile, apoptosis and cell cycle analysis revealed that gramicidin induced cell apoptosis with G2/M cell cycle inhibition. Furthermore, western blot analysis demonstrated that gramicidin down-regulated the expression of cyclinD1 and Bcl-2 as well as the FoxO1 phosphorylation. CONCLUSIONS: The current study illustrated the anti-tumor activity of gramicidin on gastric cancer cells, providing a possibility for gramicidin to be applied in clinical practice for the treatment of gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Gramicidina/farmacologia , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , Regulação para Baixo , Proteína Forkhead Box O1/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Humanos , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
4.
Anticancer Res ; 39(11): 5927-5932, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704817

RESUMO

BACKGROUND/AIM: Trastuzumab is the only clinically approved targeted therapy for HER2 gene-amplified gastric cancer at present. However, the clinical significance of multi-targeting tyrosine kinase inhibitors (TKIs) in HER2-positive gastric cancer remains unclear. MATERIALS AND METHODS: We examined the anti-tumor activity of lapatinib and afatinib, that are reversible and irreversible TKIs, in HER2 gene-amplified trastuzumab-sensitive and - resistant gastric cancer cells (GLM-1 and GLM-1HerR2) in vitro and in vivo. RESULTS: Afatinib inhibited the growth of GLM-1 and GLM-1HerR2 cells in vitro more efficiently than lapatinib by inducing G1 cell-cycle arrest and apoptosis. Preclinical studies in mice revealed that afatinib inhibited growth of intraperitoneal GLM-1 and subcutaneous GLM-1HerR2 tumor more strongly than lapatinib. Afatinib was more effective than lapatinib in blocking PI3K/Akt and MAPK signaling in both GLM-1 and GLM-1HerR2 cells. CONCLUSION: Afatinib could be a potential new molecular-targeted therapy for trastuzumab-sensitive and trastuzumab-resistant HER2 gene-amplified gastric cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/patologia , Afatinib/administração & dosagem , Animais , Apoptose , Biomarcadores Tumorais , Ciclo Celular , Movimento Celular , Proliferação de Células , Sinergismo Farmacológico , Amplificação de Genes , Humanos , Lapatinib/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(11): 6041-6047, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704830

RESUMO

BACKGROUND/AIM: We have previously reported that alternate-day S-1 had comparable effects and milder adverse events than the respective consecutive-day regimen in head and neck cancer (HNC) patients. The aim of this study was to investigate the anticancer effects of both regimens and underlying mechanisms in vitro. MATERIALS AND METHODS: Two head and neck squamous cell carcinoma (HNSCC) cell lines were treated with 5-FU given on an alternate-day or consecutive-day schedule. The relative inhibition (RI) of tumor growth was calculated. Cell cycle distributions and cyclin expression following 5-FU treatment were analyzed. RESULTS: The RI of both regimens was almost identical. The percentage of cells in S phase was significantly increased in the alternate-day group compared to the consecutive-day group (p<0.001). CONCLUSION: The cytotoxic effect of alternate-day was equivalent to that of consecutive-day. S-phase arrest was more prominently observed with the alternate-day regimen, which may help maintain 5-FU sensitivity in head and neck cancer cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Esquema de Medicação , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Técnicas In Vitro , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Células Tumorais Cultivadas
6.
Anticancer Res ; 39(11): 6049-6055, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704831

RESUMO

BACKGROUND/AIM: For patients undergoing cancer surgery, the risk for cancer progression is enhanced during the perioperative period. To what extent the type of anesthetic can affect the metastatic process and finally the outcome of patients with cancer is under debate. For this reason, the aim of this study was to investigate the effects of the volatile anesthetics sevoflurane and desflurane on colon cancer cells in vitro. MATERIALS AND METHODS: SW480 colon carcinoma cells were exposed for 3 or 6 h to sevoflurane (1 or 2.5 vol%) or desflurane (6 or 12 vol%). Cell cycle distribution was analyzed by flow cytometry after a 24-72 h recovery and apoptosis was detected by annexin V staining after a 0-48 h recovery. Viability was tested by measuring ATP content after 0 and 24 h recovery. RESULTS: Treatment with sevoflurane or desflurane caused no or only slight changes in cell-cycle distribution and apoptosis rate. Desflurane at 12vol% significantly reduced cell viability by 17±25% and 11±22% after 3 and 6 h incubation and 24 h recovery, respectively, while 2.5 vol% sevoflurane slightly increased viability. CONCLUSION: At clinically relevant concentrations, sevoflurane and desflurane had only slight effects on SW480 colon cancer cells in vitro.


Assuntos
Anestésicos Inalatórios/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Desflurano/farmacologia , Sevoflurano/farmacologia , Neoplasias do Colo/tratamento farmacológico , Humanos , Técnicas In Vitro , Células Tumorais Cultivadas
7.
Anticancer Res ; 39(11): 6057-6062, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704832

RESUMO

BACKGROUND/AIM: The prognosis of patients with osteosarcoma is poor; therefore, new treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of the 11 families (PDE1-PDE11) of the phosphodiesterase superfamily that regulates the intracellular concentrations and effects of cAMP and cGMP. This in vitro study was performed to investigate the role of PDE2 in human oral osteosarcoma HOSM-1 cells. MATERIALS AND METHODS: PDE2 expression was measured by a cAMP-PDE assay and real-time-PCR. The effects of the PDE2-specific inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 8-bromo-cAMP, and 8-bromo-cGMP on cell proliferation and migration were assessed. RESULTS: PDE2 activity and PDE2A mRNA expression were detected in HOSM-1 cells. Cell proliferation was inhibited by EHNA and 8-bromo-cAMP but not by 8-bromo-cGMP. Cell migration was stimulated by EHNA and 8-bromo-cGMP, but it was inhibited by 8-bromo-cAMP. CONCLUSION: Cell proliferation is regulated by PDE2-cAMP signaling and cell migration is regulated by PDE2-cGMP signaling in HOSM-1 cells.


Assuntos
Neoplasias Ósseas/patologia , Movimento Celular , Proliferação de Células , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Neoplasias Bucais/patologia , Osteossarcoma/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose , Compostos de Benzil/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Ciclo Celular , AMP Cíclico/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/enzimologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Transdução de Sinais , Células Tumorais Cultivadas
8.
Anticancer Res ; 39(11): 6107-6114, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704838

RESUMO

AIM: The present investigation aimed to examine the therapeutic potential of the new coumarin derivative bis(4-hydroxy-2H-chromen-2-one) coumarin (4HC) against breast cancer. MATERIALS AND METHODS: For this purpose, the effects of 4HC treatment on the proliferation of MCF-7 breast cancer cells and on MCF-10a non-cancerous cells were evaluated using a fluorescent assay. Cell cycle distribution and apoptosis were measured by image cytometry. The expression level of aromatase (CYP19A1) and apoptosis-related genes were determined by real-time PCR. RESULTS: MCF-7 mammary cancer cell proliferation was significantly decreased within 24 h after treatment with 4HC at 50 µM, while no effect was observed on the viability of MCF-10a non-cancerous mammary cells. 4HC also increased the percentage of the cells in the G2/M phase, inducing apoptosis. Real-time PCR revealed that 4HC induced MCF-7 mortality through an up-regulation of Bax and a down-regulation of Bcl-2, resulting in an increase in caspase-3 gene expression. The increased expression of apoptosis-related genes was accompanied by a decrease in CYP19A1 gene expression. CONCLUSION: 4HC selectively inhibits proliferation of MCF-7cells in vitro. Moreover, 4HC has inhibitory effects on aromatase gene expression and promoting effects on apoptosis, in MCF-7 cells.


Assuntos
Apoptose/efeitos dos fármacos , Aromatase/química , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Cromonas/química , Cumarínicos/química , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Aromatase/genética , Aromatase/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células Tumorais Cultivadas
9.
Anticancer Res ; 39(11): 6145-6153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704842

RESUMO

AIM: This study aimed to evaluate the antitumor effects of cyclolinopeptide (CL), which suppresses receptor activator of nuclear factor-κB ligand (RANKL) signalling on giant-cell tumours of the bone (GCTB) cells. MATERIALS AND METHODS: GCTB cell lines were established, and the inhibition of cell growth by CL was evaluated using the water-soluble tetrazolium salt-8 cell proliferation assay, cell cycle assay, and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay. RANKL and runt-related transcription factor 2 (RUNX2) expression levels were evaluated using real-time polymerase chain reaction before and after CL administration. RESULTS: The dose-dependent inhibition of GCTB cells was significantly pronounced in the CL-administered group compared to the non-CL-administered group (p<0.05). In the CL-administered group, the ratio of cells in the G0/G1 phase was increased, but the ratio of EdU-positive cells was decreased (p<0.05). RANKL and RUNX2 levels were decreased in the CL-administered group (p<0.05). CONCLUSION: CL has antitumor effects on GCTB in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumor de Células Gigantes do Osso/patologia , Peptídeos Cíclicos/farmacologia , Células Estromais/patologia , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/genética , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Tumorais Cultivadas
10.
Anticancer Res ; 39(11): 6155-6163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704843

RESUMO

BACKGROUND/AIM: Fluoxetine, an antidepressant, has cytotoxic effects on several cancer cell lines, while paclitaxel is an antineoplastic agent for various cancers. The aim of this study was to evaluate whether fluoxetine enhances the cytotoxic effect of paclitaxel in gastric adenocarcinoma cells and determine the mechanism of cell death. MATERIALS AND METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability and perform cell cycle analysis. Annexin V propidium iodide (PI) staining, 4',6-diamidino-2-phenylindole (DAPI) staining, caspase-3/7 assay, and western blot analysis were performed for determining cell death. RESULTS: Fluoxetine enhanced the anti-proliferative effect of paclitaxel. Fluoxetine-paclitaxel combination caused G2/M arrest and increased events in the sub G0/G1 phase in a time and dose-dependent manner, indicating apoptotic cell death. Combination treatment caused an increase in early apoptotic and late apoptotic cell death compared to single treatment alone. CONCLUSION: Fluoxetine enhanced the antiproliferation effect of paclitaxel in gastric adenocarcinoma AGS cells and the combination caused cell death by triggering apoptosis and necroptosis.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Fluoxetina/farmacologia , Necrose , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Captação de Serotonina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas
11.
Yi Chuan ; 41(10): 962-973, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31624058

RESUMO

With the improvement of growth traits and feed conversion rate, the abdominal fat rate of Chinese local breeds of broilers has been increasing. Excessive abdominal fat deposition not only reduces the slaughter rate and disease resistance of broiler chickens, but also produces waste due to the difficulty of fat treatment. In order to study the regulatory genes and pathways involved in abdominal fat deposition of broilers, we used high-fat diets to feed the Xinghua Chicken, which is a Chinese local breed. Two weeks after feeding, we found that the abdominal fat weight and rate of broilers in the high-fat diet group increased significantly, and the diameter and area of abdominal fat cells also increased significantly. Transcriptome sequencing of abdominal fat and livers showed that the differentially expressed genes in the abdominal fat were mainly enriched in the cell cycle, peroxisome proliferator- activated receptor (PPAR) and extracellular matrix (ECM) receptor signaling pathways. The differentially expressed genes in livers were also significantly enriched in the cell cycle pathway, as well as in the steroid biosynthesis and PPAR signaling pathway. By analyzing the common differentially expressed genes in abdominal fat and liver tissues, we found that these genes were also enriched in cell cycle. Finally, we used the chicken LMH (chicken hepatoma cell) cell line and chicken ICP (immortalized chicken preadipocytes) cell line to do the in vitro validation assays. We used high-fat and common medium to culture the cells. The results showed that after 48 hours, the high-fat medium could significantly promote cell cycle and increase the number of cells in S phase. Additionally, qRT-PCR results showed that the high-fat medium could significantly promote the expression of genes related to cell cycle. In conclusion, we found that high-fat diets activate the cell cycle progression of chicken hepatocytes and preadipocytes, promote cell proliferation, and then increase abdominal fat deposition.


Assuntos
Gordura Abdominal/fisiologia , Ciclo Celular , Galinhas , Transcriptoma , Animais , Linhagem Celular , Proliferação de Células , Perfilação da Expressão Gênica , Receptores Ativados por Proliferador de Peroxissomo , Receptores de Superfície Celular , Transdução de Sinais
12.
Br J Radiol ; 92(1104): 20190672, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31603350

RESUMO

OBJECTIVE: This paper considers aspects of radiobiology and cell and tissue kinetics applicable to legal disputations concerned with diagnostic and treatment onset delays. METHODS: Various models for tumour volume changes with time are reviewed for estimating volume ranges at earlier times, using ranges of kinetic parameters. Statistical cure probability methods, using Poisson statistics with allowances for parameter heterogeneity, are also described to estimate the significance of treatment delays, as well as biological effective dose (BED) estimations of radiation effectiveness. RESULTS: The use of growth curves, based on parameters in the literature but with extended ranges, can identify a window of earlier times when such tumour volumes would be amenable to a cure based on the literature for curability with stage (and dimensions). Also, where tumour dimensions are not available in a post-operative setting, higher cure probabilities can be achieved if treatment had been given at earlier times. CONCLUSION: The use of radiobiological modelling can provide useful insights, with quantitative assessments of probable prior conditions and future outcomes, and thus be of assistance to a Court in deciding the most correct judgement. ADVANCES IN KNOWLEDGE: This study collates prior knowledge about aspects of radiobiology that can be useful in the accumulation of sufficient proof within medicolegal claims involving diagnostic and treatment days.


Assuntos
Diagnóstico Tardio/legislação & jurisprudência , Neoplasias/diagnóstico , Neoplasias/radioterapia , Radiobiologia/legislação & jurisprudência , Tempo para o Tratamento/legislação & jurisprudência , Algoritmos , Biomarcadores Tumorais/análise , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Estadiamento de Neoplasias , Neoplasias/patologia , Distribuição de Poisson , Resolução de Problemas , Prognóstico , Radioterapia (Especialidade)/legislação & jurisprudência , Radioterapia (Especialidade)/métodos , Radiobiologia/métodos , Eficiência Biológica Relativa , Fatores de Tempo , Carga Tumoral/fisiologia
13.
Life Sci ; 237: 116945, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605710

RESUMO

AIM: Over-expression of histone deacetylase 8 (HDAC8) has been demonstrated in breast cancer. But the underlying molecular mechanism of HDAC8 on the progression of breast cancer remains unknown. MicroRNAs (miRs) are proposed as important molecules in cancer progression by targeting specific oncogenes or tumor-suppressor genes. Our overall objective was to assess the miR-216b-5p role on HDAC8; and its impacts on breast cancer (BC) progression. MAIN METHODS: We acquired cancerous and noncancerous tissues from Iran Tumor Bank (I.T.B). The MDA-MB-231, MCF-7 and MCF-10A BC cell lines were also purchased. The tissue and cell line expression levels of miR-216b-5p and HDAC8 were determined by quantitative real-time PCR (qPCR). We next measured protein levels of HDAC8 by Western blotting assay. The cell cycle, cell proliferation, and colony formation assay were determined. Finally, we investigated the role of HDAC8 using a knockout vector; and confirmed the targeting of 3' untranslated region (3'-UTR) of HDAC8 through miR-216b-5p using a luciferase reporter assay. KEY FINDINGS: Our results demonstrated a significant decrease in miR-216b-5p, and remarkable increase in HDAC8 levels within human breast cancer tissues and cell lines. The lower levels of miR-216b-5p were negatively correlated with lymph node metastasis and advanced tumor size. The overexpression of miR-216b-5p in BC cell lines inhibited cellular proliferation and progression. HDAC8 was directly down-regulated by miR-216b-5p and knockout of HDAC8 showed the similar effects as miR-216b-5p overexpression. SIGNIFICANCE: Briefly, HDAC8 is an oncogene that accelerate breast cancer proliferation and progression and miR-216b-5p modulates those functions by binding to HDAC8 3'-UTR.


Assuntos
Neoplasias da Mama/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , MicroRNAs/genética , Proteínas Repressoras/metabolismo , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular , Regulação para Baixo , Feminino , Histona Desacetilases/genética , Humanos , Prognóstico , Proteínas Repressoras/genética , Células Tumorais Cultivadas
14.
Int J Nanomedicine ; 14: 7123-7139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564869

RESUMO

Background: Poly(amidoamine) (PAMAM) dendrimers are of considerable interest when used as a carrier for topical drugs for the skin, although little is known about their possible side effects. Therefore, our study was about the impact of 2nd and 3rd generation PAMAM dendrimers on human keratinocytes and fibroblasts cells. Methods: The effect of the tested compounds on collagen biosynthesis was determined using 5[3H]-proline incorporation bioassay. Morphological changes accompanying cell growth inhibition were observed using a confocal microscope. To evaluate the percentage of apoptotic/necrotic cells and the cell growth dynamic of apoptotic features, we performed Annexin V/PI double staining assay, assessed caspase activity, and performed cell cycle analysis by flow cytometry. The flow cytometry method was also used to determine the effect of dendrimers on pro-inflammatory cytokines (IL-6, IL-8 IL-1ß). Results: The obtained results showed that as the concentration and the generation of dendrimers increased, collagen biosynthesis decreased. We also observed abnormalities in cell differentiation, which may have caused disturbed secretion of pro-inflammatory cytokines. We found that dendrimers cause chronic inflammation which may cause adverse changes in the skin, ultimately- leading to apoptosis in the case of dendrimers in lower concentrations or necrosis at higher concentrations (especially 3rd generation dendrimers). In addition, the inflammatory path induced by the tested compounds was caused by damage in the mitochondria, which we observed as a significant decrease in the mitochondrial membrane potential. Conclusion: The results of our study showed that PAMAM dendrimers can cause disorders of cell proliferation and differentiation and may be the cause of cell cycle deregulation and chronic adverse inflammation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Dendrímeros/farmacologia , Fibroblastos/metabolismo , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Colágeno/biossíntese , Dendrímeros/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fluorescência , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Necrose
15.
Anticancer Res ; 39(10): 5297-5310, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570424

RESUMO

BACKGROUND/AIM: Low-molecular weight heparins (LMWHs) may possess putative antitumoral properties; however, the underlying mechanism(s) remains elusive. We evaluated the antiproliferative and antimigratory effects of enoxaparin (a LMWH) in lung adenocarcinoma A549 cells, and assessed the possible mechanism involved, and the effect on doxorubicin's efficacy. MATERIALS AND METHODS: Proliferation and migration were evaluated using BrdU and transwell assays, respectively. Immunoblotting was used to measure PAR-1, PAR-2, MMP-2, ERK1/2 and Akt proteins. Apoptosis and cell cycle studies examined the combined effect of enoxaparin and doxorubicin. RESULTS: Enoxaparin inhibited A549 cell proliferation and migration. Following PAR-1 gene knock down, enoxaparin's effect on A549 cell proliferation was diminished compared to scrambled siRNA. Our experiments verified that enoxaparin-mediated down-regulation of MAPK and PI3K, reduced MMP-2 expression and inhibited A549 cell migration. Additionally, enoxaparin increased doxorubicin's efficacy by enhancing apoptosis, while no effect on cell-cycle progression was observed. CONCLUSION: Results suggest that the anticancer activity of enoxaparin in A549 cells was mediated by the interference of two major PAR-1 downstream signaling pathways, MAPK/ERK and PI3K/Akt, which in turn inhibit proliferation and migration. Therefore, enoxaparin may be promising as an adjunct to traditional chemotherapy for lung cancer and warrants further investigation.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Enoxaparina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptor PAR-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo
16.
Anticancer Res ; 39(10): 5311-5327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570425

RESUMO

BACKGROUND/AIM: MiR-221, often described both as an oncogenic microRNA and as a tumour suppressor, targets mRNAs involved in carcinogenesis. While other oncogenic microRNAs showed correlations with prostate cancer cell lines' aggressiveness, miR-221 showed an unusual overexpression in PC3. MATERIALS AND METHODS: CRISPR was used to delete miR-221 from PC3 cells. Analysing the characteristics of PC3miR-221del cells, a reduced growth rate and expression of cell-cycle genes was observed. In global gene expression/ontology analysis of PC3miR-221del cells, cell-cell and cell-substrate adhesion pathways were found to be greatly affected. In addition, reduced levels of adhesion, invasion and motility for PC3miR-221del cells, a change in F-actin localisation and a reduction of EMT markers were observed. RESULTS: The tumour suppressor gene, DIRAS3, was a predicted target of miR-221. In PC3miR-221del cells DIRAS3 was up-regulated at the gene and protein level. Ectopic expression of DIRAS3 in PC3wt cells recapitulated the cellular morphology changes seen in PC3miR-221del cells. DIRAS3 3'UTR was more stable in PC3miR-221del cells, as measured by semi-quantitative PCR and luciferase fusion reporter assays. CONCLUSION: MiR-221 promotes aggressiveness of PC3 cells by down-regulating DIRAS3, and promoting epithelial-to-mesenchymal transition.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Oncogenes/genética , Células PC-3 , Neoplasias da Próstata/genética , Regulação para Cima/genética , Proteínas rho de Ligação ao GTP/genética
17.
Int J Nanomedicine ; 14: 7489-7502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571860

RESUMO

Background: 3,5,4'-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated. Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated. Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues. Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Micelas , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Disponibilidade Biológica , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Camundongos Endogâmicos BALB C , Fosfatidiletanolaminas/efeitos adversos , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Polímeros/química , Ratos Sprague-Dawley , Resultado do Tratamento
18.
Adv Exp Med Biol ; 1164: 199-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576550

RESUMO

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.


Assuntos
Ciclo Celular , Neoplasias , Ciclo Celular/fisiologia , Humanos , Neoplasias/fisiopatologia , Células-Tronco Neoplásicas/citologia
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 546-550, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642233

RESUMO

OBJECTIVE: To investigate the expression of stearoyl-CoA desaturase-1 (SCD1) in breast cancer cell lines. To analyze the effect of inhibiting SCD1 activity on the proliferation and cell cycle of MCF-7 breast cancer cell and its mechanism. METHODS: The expression of SCD1 protein were detected by Western blot techniques in breast cancer cell lines and humanskin fibroblasts.Cell viability of MCF-7 cells treated with MF-438 was measured using MTS assay and IC50 value was calculated.The distribution of cell cycle was determined by PI staining using flow cytometry.The expression of Cyclin D1 was detected by Western blot. The expression of Akt, pAkt, pAMPK and pACC were also detected by Western blot. RESULTS: The expression level of SCD1 in MCF-7 and MDA-MB-231 cells was significantly higher than that in HSF cells (P < 0.05).MF-438 showed a significant dose-dependent proliferation inhibition effect on MCF-7 cells cultured in low serum at a concentration ranging from 100 nmol/L to 100 µmol/L with an IC50 value of (3.9±0.45) µmol/L. After intervention of 5 µmol/L MF-438 in MCF-7 cells, the proportion of cells in S phase and G2/M phase was significantly decreased (P < 0.01), the proportion of cells in G0/G1 phase increased (P < 0.01), and the expression of Cyclin D1 was significantly decreased (P < 0.05); Meanwhile, the expression of pAkt and pAkt/Akt value were significantly decreased (P < 0.05) and the expression of pAMPK and pACC levels were significantly increased (P < 0.05). CONCLUSIONS: SCD1 plays an important role in the occurrence and development of breast cancer. Inhibition of SCD1 activity can inhibit cell cycle progression and impair cell proliferation by down-regulating the Akt pathway and activating the AMPK pathway. Further research on SCD1 is expected to provide a new target for molecular targeted therapy of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Estearoil-CoA Dessaturase/genética , Divisão Celular , Ciclina D1/metabolismo , Humanos , Células MCF-7 , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estearoil-CoA Dessaturase/antagonistas & inibidores
20.
Georgian Med News ; (292-293): 87-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560670

RESUMO

Hematological disorders caused by radiation remain the most challenging problem of the last decades. Environmental radiation, as well as medical application of radiation causes serious problems especially from the point of view of blood formation and passage of blood functional cells. Bone marrow emptying followed by the rise of immature cells in the bloodstream is the main pathology that must be eliminated. The importance of the issue is well recognized by all investigators. Opening of agents for regulation of spontaneous regeneration of hematopoietic cell lines is of prime importance in cancer treatment. Ubiquitin is a globular protein of eukaryotic cells. It is involved in regulation of cell cycle. Recently we studied the influence of extracellular ubiquitin on regeneration of leukopoiesis. Interestingly what is its effect on erythropoietic cell lines? Erythrocytes are more resistant to irradiation, than nucleic cells. Their depletion-elevation picks during blood regeneration clearly reveal low sharpness. Nevertheless, depletion of erythropoietic cells if not treated, may cause short- and long-term side effects. We studied the influence of intraperitoneally injected ubiquitin on the process of spontaneous regeneration of erythropoietic cell lines of bone marrow (BM) and peripheral blood (PB) after irradiation in mice. The source of radiation was 137Cs with dose rate 1Gy/min., the duration of exposure 3 min and 5 min. Nonlinear white mice of 22±2 gr. were used for experiment. Animals were divided into five groups (6 animals in each group): the first control group of intact mice; the second test group of mice irradiated by the sublethal dose of 3Gy; the third test group of mice irradiated by 3Gy intraperitoneally injected by ubiquitin by the dose of 100µg/ml at the 72 hour point after irradiation; the fourth test group of mice irradiated by the dose of LD50 5Gy; the fifth test group of mice irradiated by 5Gy intraperitoneally injected by ubiquitin at the 72 hour point after irradiation. PB and BM samples from the control group and the test groups of mice have been taken every 24 hours after irradiation during 7 days. Microscopy and statistical methods have been implicated for calculation of cell count of PB and BM. Analyzing the results we concluded that Ubiquitin prevents depletion-elevation picks of erythrocytes and erythroblasts regardless of the severity of damage caused by different doses of radiation indicating normalization of the regeneration process after irradiation. The study is important for opening new therapeutic agents for normalization of regeneration hematopoiesis after irradiation.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Radioisótopos de Césio , Hematopoese/efeitos dos fármacos , Lesões Experimentais por Radiação , Regeneração/efeitos dos fármacos , Ubiquitina/farmacologia , Animais , Ciclo Celular/efeitos da radiação , Camundongos , Ubiquitina/administração & dosagem
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