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1.
Anticancer Res ; 40(1): 229-238, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892571

RESUMO

BACKGROUND/AIM: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. RESULTS: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. CONCLUSION: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.


Assuntos
Neoplasias da Mama/patologia , Curcumina/farmacologia , Progressão da Doença , Naftoquinonas/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/uso terapêutico , Matriz Extracelular/metabolismo , Feminino , Humanos , Células MCF-7 , Naftoquinonas/química , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Anticancer Res ; 39(11): 6115-6123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704839

RESUMO

BACKGROUND/AIM: Colon cancer is the second most common deadliest malignancy in the world and better understanding of its underlying mechanisms is needed to improve clinical management. Natural plant extracts are gaining attention in the development of new therapeutic strategies against various cancer types. Shikonin is a naturally extracted naphthoquinone pigment with effects against cancer, including colon cancer. MATERIALS AND METHODS: In this study, we conducted a series of in vitro experiments to show the effects of Shikonin on colon cancer cell apoptosis. A colon cancer cell line with overexpression of peroxiredoxin V (PrxV) was constructed and the relationship of PrxV expression with Shikonin-induced cell apoptosis was investigated. RESULTS: Shikonin induced colon cancer cell apoptosis via regulation of mammalian target of rapamycin signaling. Shikonin-induced cell apoptosis was abrogated by overexpression of PrxV. CONCLUSION: According to the results obtained in this study, targeting PrxV may provide new insight for the successful management of colon cancer by inducing cell apoptosis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Naftoquinonas/farmacologia , Peroxirredoxinas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Humanos , Células Tumorais Cultivadas
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.
Chem Biol Interact ; 314: 108841, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586452

RESUMO

Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC50 values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/química , Complexos de Coordenação/farmacologia , Triterpenos/química , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Glioma/metabolismo , Glioma/patologia , Humanos
5.
Chem Biol Interact ; 314: 108846, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606474

RESUMO

Matrix metalloproteinases (MMPs) have been implicated in EMT but their role in the regulation of cigarette smoke-induced EMT in airway epithelium is not clear. We have therefore investigated the potential role of MMP-2 and -9 in cigarette smoke extract (CSE) induced EMT using A549 lung epithelial cells and human small airway epithelial cells (SAEC). The cells were treated with different concentration of CSE, and MTT and trypan blue assays, acridine orange-ethidium bromide assay, gelatin zymography, Western blotting, immunofluorescence studies, Boyden-chamber assay, wound healing assay and air-liquid interface (ALI) culture were used to assess different cellular and molecular changes associated with EMT. The results depict that CSE increased the cytotoxicity along with a concurrent increase in the expression and activity of MMP-2 and -9. CSE further altered EMT markers like E-cadherin, N-cadherin, vimentin, and the molecular modulators of EMT such as ß-catenin and pGSK-3ß. Further, CSE also upregulated EGFR, AKT, and ERK1/2 in airway epithelial cells. SB-3CT, a known inhibitor of MMP-2 and -9, altered and reversed the expression of markers of EMT and kinases, validating the role of MMP-2 and -9 in CSE-induced EMT. Fisetin, a plant-derived bioflavonoid, also reversed the expression of EMT markers and molecular regulators in a similar fashion as SB-3CT. In summary, this study highlights the role of MMP-2 and -9 in CSE-induced EMT and curate its molecular cascade through EGFR/AKT/ERK/ß-catenin axis, which could be restored by MMP-2 and -9 inhibitor and fisetin. Fisetin is hitherto unknown to modulate CSE-induced MMPs activity in airway epithelial cells, and our study suggests its potential role as a therapeutic approach in CSE-induced EMT in lung epithelial cells.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavonoides/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fumaça/efeitos adversos , Tabaco/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo
6.
J Cancer Res Clin Oncol ; 145(12): 2921-2936, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620898

RESUMO

PURPOSE: The present study aims to determine whether co-targeting PI3K/Akt and MAPK/ERK pathways in human hypopharyngeal squamous cell carcinoma (HSCC) is a potential anticancer strategy. METHODS: We retrospectively analyzed the clinical data of HSCC patients, and the phosphorylation status of Akt and Erk in HSCC and tumor adjacent tissues was evaluated by immunohistochemistry. MTT and colony formation assay were performed to determine the anti-proliferative effect of PI3K/mTOR inhibitor GDC-0980 and MEK inhibitor Refametinib on HSCC cell line Fadu. Wound-healing and Transwell migration assay were used to analyze the anti-migrative capability of the two drugs. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. The combinational anticancer effect of GDC-0980 and Refametinib was evaluated according to Chou and Talalay's method. RESULTS: The levels of p-Akt and p-Erk were increased significantly with the progression of clinical stage of HSCC, suggesting PI3K/Akt and MAPK/ERK pathways might be associated with HSCC occurrence and progression. Furthermore, both GDC-0980 and Refametinib showed obvious antitumor effects on FaDu cells. Treatment by the two drugs arrested FaDu cell cycle progression in G1 phase, with reduction of cyclin D1 and p-Rb, in contrast to enhancement of p27. GDC-0980 inhibited FaDu cell migration and reduced metastasis related proteins including p-PKCζ, p-Integrin ß1 and uPA. Combination use of GDC-0980 and Refametinib exhibited strong synergistic anti-tumor effect. CONCLUSION: Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCC patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Sinergismo Farmacológico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Estudos Retrospectivos , Sulfonamidas/farmacologia
7.
Cell Physiol Biochem ; 53(4): 713-730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31599538

RESUMO

BACKGROUND/AIMS: Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damage. The overactivation of the renin-angiotensin system mainly by angiotensin II (AII) seems to be a main contributor to progressive renal fibrosis. Epithelial to mesenchymal transition (EMT) is a mechanism that promotes renal fibrosis. Owing to heat shock protein 70 (Hsp70) cytoprotective properties, the chaperone exhibits an important potential as a therapeutic target. We investigate the role of Hsp70 on Angiotensin II induced epithelial mesenchymal transition within the Losartan effect in proximal tubule cells (PTCs) from a genetic model of hypertension in rats (SHR). METHODS: Primary cell culture of PTCs from SHR and Wistar Kyoto (WKY) rats were stimulated with AII, treated with Losartan (L), (L+AII) or untreated (Cc). The functional Hsp70 role in Losartan effect, after silencing its expression by cell transfection, was determined by Immunofluorescence; Western blotting; Gelatin Zymography assays; Scratch wound assays; flow cytometry; and Live Cell Time-lapse microscopy. RESULTS: (L) and (L+AII) treatments induced highly organized actin filaments and increased cortical actin in SHR PTCs. However, SHR PTCs (Cc) and (AII) treated cells showed disorganized actin. After Hsp72 knockdown in SHR PTCs, (L) was unable to stabilize the actin cytoskeleton. We demonstrated that (L) and (L+AII) increased E-cadherin levels and decreased vinculin, α-SMA, vimentin, pERK, p38 and Smad2-3 activation compared to (AII) and (Cc) SHR PTCs. Moreover, (L) inhibited MMP-2 and MMP-9 secretion, reduced migration and cellular displacement, stabilizing intercellular junctions. Notably, (L) treatment in shHsp72 knockdown SHR PTCs showed results similar to SHR PTCs (Cc). CONCLUSION: Our results demonstrate that Losartan through Hsp70 inhibits the EMT induced by AII in proximal tubule cells derived from SHR.


Assuntos
Angiotensina II/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Losartan/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Adesões Focais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vinculina/metabolismo
8.
Int J Nanomedicine ; 14: 7609-7624, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571866

RESUMO

Background: Iron oxide nanoparticles (IONs) have been increasingly utilized in a wide spectrum of biomedical applications. Surface coatings of IONs can bestow a number of exceptional properties, including enhanced stability of IONs, increased loading of drugs or their controlled release. Methods: Using two-step sonochemical protocol, IONs were surface-coated with polyoxyethylene stearate, polyvinylpyrrolidone or chitosan for a loading of two distinct topo II poisons (doxorubicin and ellipticine). The cytotoxic behavior was tested in vitro against breast cancer (MDA-MB-231) and healthy epithelial cells (HEK-293 and HBL-100). In addition, biocompatibility studies (hemotoxicity, protein corona formation, binding of third complement component) were performed. Results: Notably, despite surface-coated IONs exhibited only negligible cytotoxicity, upon tethering with topo II poisons, synergistic or additional enhancement of cytotoxicity was found in MDA-MB-231 cells. Pronounced anti-migratory activity, DNA fragmentation, decrease in expression of procaspase-3 and enhancement of p53 expression were further identified upon exposure to surface-coated IONs with tethered doxorubicin and ellipticine. Moreover, surface-coated IONs nanoformulations of topo II poisons exhibited exceptional stability in human plasma with no protein corona and complement 3 binding, and only a mild induction of hemolysis in human red blood cells. Conclusion: The results imply a high potential of an efficient ultrasound-mediated surface functionalization of IONs as delivery vehicles to improve therapeutic efficiency of topo II poisons.


Assuntos
Materiais Revestidos Biocompatíveis/química , DNA Topoisomerases Tipo II/metabolismo , Liberação Controlada de Fármacos , Compostos Férricos/química , Nanopartículas/química , Sonicação/métodos , Inibidores da Topoisomerase II/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Cinética , Masculino , Eletricidade Estática , Propriedades de Superfície , Cicatrização/efeitos dos fármacos
9.
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
10.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
J Cancer Res Clin Oncol ; 145(12): 2951-2967, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31654121

RESUMO

PURPOSE: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide and new improvements are urgently needed. Several miRNA-targeted therapeutics have reached clinical development. MicroRNA-143 (miR-143) was found to significantly suppress the migration and invasion of NSCLC. It might be of great potential for NSCLC treatment. However, the therapeutic effect of miR-143 against NSCLC in vivo has not been explored until now. METHODS: The cationic liposome/pVAX-miR-143 complex (CL-pVAX-miR-143) was prepared and its biodistribution was assessed. The tumor suppression effects of CL-pVAX-miR-143 were evaluated in early-stage and advanced experimental lung cancer metastasis mice models by systemic delivery, respectively, and also in subcutaneous tumor models by intratumoral injection. The toxicity of CL-pVAX-miR-143 was assessed by H&E analysis and biochemical measurements. The preliminary mechanism of CL-pVAX-miR-143 on tumor suppression was explored by immunochemistry and western blotting. RESULTS: The assays on the stability and safety of CL-pVAX-miR-143 showed that it mainly accumulated in the lung after systemic administration. The intratumoral delivery of CL-pVAX-miR-143 effectively inhibited A549 subcutaneous tumor growth. Notably, systemic delivery of CL-pVAX-miR-143 significantly inhibited tumor metastasis and prolonged survival dose dependently in early-stage experimental lung cancer metastasis models. More importantly, same results were shown in advanced mice models with metastasis. CL-pVAX-miR-143 treatment did not induce obvious acute toxicity. The preliminary mechanism on inhibiting tumor metastasis might be induced by targeting CD44v3. CONCLUSIONS: Our results suggested that CL-pVAX-miR-143 might be a promising strategy for clinical treatment of non-small cell lung cancer, especially for advanced NSCLC with metastasis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cátions/administração & dosagem , Lipossomos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/administração & dosagem , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Tecidual
12.
Chem Commun (Camb) ; 55(86): 12904-12907, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31584577

RESUMO

A novel type of hydrogen peroxide (H2O2)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H2O2-responsive behaviour of KA-NO-4 was thoroughly investigated. The NO-centered mechanism of action of KA-NO-4 was intracellularly studied.


Assuntos
Amidas/química , Antineoplásicos/química , Compostos Azo/química , Peróxido de Hidrogênio/química , Doadores de Óxido Nítrico/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia
13.
Braz J Med Biol Res ; 52(10): e8385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618367

RESUMO

Malignant melanoma (MM) is one of the malignant tumors with highly metastatic and aggressive biological actions. Schizandrin A (SchA) is a bioactive lignin compound with strong anti-oxidant and anti-aging properties, which is stable at room temperature and is often stored in a cool dry place. Hence, we investigated the effects of SchA on MM cell line A375 and its underlying mechanism. A375 cells were used to construct an in vitro MM cell model. Cell viability, proliferation, apoptosis, and migration were detected by Cell Counting Kit-8, BrdU assay, flow cytometry, and transwell two-chamber assay, respectively. The cell cycle-related protein cyclin D1 and cell apoptotic proteins (Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9) were analyzed by western blot. Alteration of H19 expression was achieved by transfecting with pEX-H19. PI3K/AKT pathway was measured by detecting phosphorylation of PI3K and AKT. SchA significantly decreased cell viability in a dose-dependent manner. Furthermore, SchA inhibited cell proliferation and cyclin D1 expression. SchA increased cell apoptosis along with the up-regulation of pro-apoptotic proteins (cleaved-caspase-3, cleaved-caspase-9, and Bax) and the down-regulation of anti-apoptotic protein (Bcl-2). Besides, SchA decreased migration and down-regulated matrix metalloproteinases (MMP)-2 and MMP-9. SchA down-regulated lncRNA H19. Overexpression of H19 blockaded the inhibitory effects of SchA on A375 cells. SchA decreased the phosphorylation of PI3K and AKT while H19 overexpression promoted the phosphorylation of PI3K and AKT. SchA inhibited A375 cell growth, migration, and the PI3K/AKT pathway through down-regulating H19.


Assuntos
Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Lignanas/farmacologia , Melanoma/patologia , Compostos Policíclicos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
14.
Life Sci ; 235: 116817, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476309

RESUMO

AIMS: In the tumor microenvironment, dysregulated immune cells could promote tumor progression, invasion and metastasis, by establishing a symbiotic relationship with cancer cells. A pivotal role is played by monocyte recruitment and induction of tumor-associated macrophages (TAMs), which provide immunosuppression and tumorigenesis. The effect of nemorosone, an antiproliferative phytocomponent present in Cuban Propolis, on TAM-induced tumor progression remains to be elucidated. Here we investigated the symbiotic relationship between monocytic leukemia THP-1 and hepatocellular carcinoma HepG2 cells, and the role of nemorosone in preventing TAM-induced tumor growth. MAIN METHODS: Macrophage differentiation induced by HepG2-conditioned medium was assessed by flow cytometry, analysis of secreted molecules and cytokine expression. The effect of nemorosone and/or conditioned THP-1-medium on HepG2 proliferation was evaluated by MTT assay, colony formation, cells cycle and migration assays. KEY FINDINGS: HepG2 cells induced THP-1 recruitment and differentiation to macrophages. When compared with control THP-1 cells, differentiated THP-1 showed a significant increase of the matrix metalloproteinases MMP-2 and MMP-9 expression (P < 0.01), and slightly induced HepG2 cells growth. This effect was counteracted by nemorosone, which also significantly inhibited colony formation (P < 0.01) and migratory capacity of HepG2 cells, driving a high percentage of cells (80%) to the G0/G1 phase. SIGNIFICANCE: HepG2-conditioned medium is a suitable model for THP-1 modulation and differentiation. Moreover, nemorosone significantly inhibits the proliferation of HepG2 cells, both in presence and absence of the soluble factors secreted by TAMs. Further studies are needed to elucidate the role of this natural compound in the HCC-TAM relationship.


Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Monócitos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
15.
Life Sci ; 235: 116831, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31487530

RESUMO

AIMS: TRAF6 is an intracellular signal adapter molecule plays a significant role in tumor development. However, the specific mechanism causes and promotes of colorectal cancer keep largely unknown. Therefore, we sought to investigate the roles and the molecular mechanisms of TRAF6 in regulation colorectal cancer. MATERIAL AND METHODS: The immunohistochemistry analyzed the expression of TRAF6 in colorectal cancer samples and analyzed the effects of expression of TRAF6 on the prognosis in colorectal cancer. The roles of TRAF6 in regulating colorectal cancer cell proliferation, colony formation, cell migration, cell wound healing and cell invasion were evaluated in vitro. Animal studies were performed to investigate the effects of TRAF6 on tumor growth. mRNA abundance of key genes was analyzed via qPCR. Protein level of TRAF6 and NF-κB/AP-1 signaling pathways was examined by Western blot. Luciferase reporter and Immunofluorescence assays were used to identify the activities NF-κB/AP-1 signaling pathways. KEY FINDINGS: TRAF6 high expression in colorectal cancer tissues. And colorectal cancer patients with high expression of TRAF6 had a poor survival rate. TRAF6 knockdown can inhibit proliferation, migration, and invasion of colorectal cancer cells in vitro and in vivo experiments. TRAF6 activates the TRAF6-NF-κB/AP-1 signaling pathway by entering the nucleus, causing biobehavioral changes in colorectal cancer cells. SIGNIFICANCE: TRAF6 plays a vital role in the progression of colorectal cancer. What's more, research elucidating the biological mechanisms of TRAF6 can treated as potential therapeutic target for colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Colorretais/fisiopatologia , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/fisiologia , Ensaio Tumoral de Célula-Tronco , Cicatrização/fisiologia
16.
Anticancer Res ; 39(9): 4845-4851, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519587

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) constitutes 15-20% of all breast carcinomas, affecting younger women more often and has a worse prognosis than other types of breast cancer, due to the combination of more aggressive clinical behavior and lack of molecular targets for therapy. This study assessed the effects of non-genotoxic concentrations of tributyltin isothiocyanate (TBT-ITC) and triphenyltin isothiocyanate (TPT-ITC) on MDA-MB-231 cells. MATERIALS AND METHODS: MTT assay, comet assay, kinetic imaging and flow cytometry were used for analysis of MDA-MB-231 cells. RESULTS: The results showed that 100 nM concentration of TBT-ITC and TPT-ITC, that did not affect viability or DNA integrity, slowed-down migration by CD44 down-regulation. Moreover, both compounds demonstrated immunomodulatory properties, attenuating PD-L1 expression in MDA-MB-231 cells. CONCLUSION: TPT-ITC was more effective in down-regulating CD44 expression and reducing migration than TBT-ITC, while TBT-ITC was more potent in lowering PD-L1 expression in comparison with TPT-ITC.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais , Movimento Celular/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Imunofenotipagem , Isotiocianatos/química , Compostos Orgânicos de Estanho/química
17.
Toxicol Lett ; 316: 49-59, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520698

RESUMO

Epidemiological studies have established the correlations between PM2.5 and a wide variety of pulmonary diseases. However, their underlying pathogeneses have not been clearly elucidated yet. In the present study, the epithelial-mesenchymal transition (EMT) phenotype with enhanced proliferation and migration activity of human pulmonary epithelial cell line BEAS-2B was observed after exposure to low dose PM2.5 exposure (50 µg/ml) for 30 passages. Then, epithelial cells derived-exosomal micro-RNA (miRNA) and intracellular total RNA were extracted, and the differentially expressed exosomal miRNAs (DE-Exo-MiRs) as well as differentially expressed protein coding genes (DEGs) were identified by RNA sequencing (RNA-seq) and transcriptome analysis. We found that chronic PM2.5 exposure stimulated the release of pulmonary epithelium derived exosomes. 45 DE-Exo-MiRs including 32 novelly predicted miRNAs and 843 DEGs between PM2.5 exposed group and the normal control were detected. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in extracellular matrix organization, focal adhesion and cancer related terms. Besides, the enrichment analyses on 7774 mRNA targets of 27 DE-Exo-MiRs predicted by MiRanda software also revealed the potential regulatory role of exosomal miRNAs in pathways in cancer, Wingless/Integrated (Wnt) signaling pathway, focal adhesion related genes and other multiple pathogenic pathways. Moreover, the interactive exosomal miRNA-mRNA pair networks were constructed using Cytoscape software. Our results provided a novel basis for a better understanding of the mechanisms of chronic PM2.5 exposure induced pulmonary disorders including pulmonary fibrosis and cancer, in which exosomal miRNAs (Exo-MiRs) potentially functions by dynamically regulating gene expressions.


Assuntos
Células Epiteliais/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Pulmão/efeitos dos fármacos , MicroRNAs/genética , Material Particulado/toxicidade , RNA Mensageiro/genética , Transcriptoma/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Biologia Computacional , Bases de Dados Genéticas , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Redes Reguladoras de Genes , Humanos , Pulmão/metabolismo , Pulmão/ultraestrutura , MicroRNAs/metabolismo , Tamanho da Partícula , RNA Mensageiro/metabolismo , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Crônica
18.
Medicine (Baltimore) ; 98(36): e17009, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490383

RESUMO

Erythrina corallodendron L., a kind of landscape tree, has long been used as a traditional medicine. In this study, the composition of essential oil extracted from the leaves was analysed by GC-MS (gas chromatograph-mass spectrometer), with linalool identified as the main compound. Its cytotoxicity against MDA-MB-231, MCF-7 and HMLE cells was examined by MTT and cloning assays. Transwell and wound-healing assays were used to examine the inhibition of migration and invasion. Western blot, qRT-PCR and immunofluorescence staining were used to measure the mRNA and protein expression of factors related to EMT (snail, slug, E-cadherin, N-cadherin and vimentin). The essential oil of Erythrina corallodendron leaves was found to inhibit the proliferation, migration and invasion of breast cancer cells in a dose-dependent manner. The findings of this study suggest that the essential oil of E. corallodendron leaves may merit further investigation as a potential clinical or adjuvant drug for treating breast cancer migration and invasion.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/análise , Neoplasias da Mama/tratamento farmacológico , Erythrina/química , Óleos Voláteis/uso terapêutico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Células MCF-7 , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Fitoterapia , Folhas de Planta/química
19.
Life Sci ; 235: 116832, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31491455

RESUMO

AIMS: Delineates the role of TIS111D in bladder cancer. MATERIALS AND METHODS: The expression of TIS111D in bladder cancer and adjacent tissues was assessed by immunohistochemistry, Western blot and real-time PCR. Western blot and real-time PCR were used to analyse the expression of TIS111D in HT1197, T24, 5637 and TCCSUP cells. After TIS111D was silenced in T24, 5637 and TCCSUP cells, MTT and Transwell assays were used to detect the effects of TIS111D on proliferation and migration. Western blot and real-time PCR were used to detect the regulatory effect of downregulation of TIS111D on N-cad and E-cad. In vivo experiments confirmed the role of TIS111D in the growth and migration of bladder cancer and determined whether the role of TIS111D in bladder cancer is related to its regulation of N-cad and E-cad. KEY FINDINGS: The expression of TIS11D was higher in tumour tissues and bladder cancer cells. Si-TIS111D could inhibit the growth and migration of bladder cancer cells, while TIS111D could regulate the expression of E-cad and N-cad to regulate epithelial-mesenchymal transition (EMT). We also demonstrated that TIS111D could promote the growth and migration of bladder cancer in vivo by regulating EMT. SIGNIFICANCE: TIS111D may participate in the regulation of bladder cancer progression by regulating EMT.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Neoplasias da Bexiga Urinária/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo , Humanos , RNA Interferente Pequeno/farmacologia
20.
Inorg Chem ; 58(20): 14175-14184, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31559820

RESUMO

A series of ferrocene-appended half-sandwiched iridium(III) phenylpyridine complexes have been designed and synthesized. These complexes show better anticancer activity than cisplatin widely used in clinic under the same conditions. Meanwhile, complexes could effectively inhibit cell migration and colony formation. Complexes could interact with protein and transport through serum protein, effectively catalyzing the oxidation of nicotinamide-adenine dinucleotid and inducing the accumulation of reactive oxygen species (ROS, 1O2), which confirmed the anticancer mechanism of oxidation. Furthermore, laser scanning confocal detection indicates that these complexes can enter cells followed by a non-energy-dependent cellular uptake mechanism, effectively accumulating in the lysosome (Pearson's colocalization coefficient: ∼0.90), leading to lysosome damage, and reducing the mitochondrial membrane potential (MMP). Taken together, ferrocene-appended iridium(III) complexes possess the prospect of becoming a new multifunctional therapeutic platform, including lysosome-targeted imaging and anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Ferrosos/farmacologia , Irídio/farmacologia , Metalocenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Irídio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metalocenos/química , Estrutura Molecular , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
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