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1.
Cancer Lett ; 474: 94-105, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954771

RESUMO

Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, participates in protecting cells from electrophilic or oxidative stresses through regulating expression of cytoprotective and antioxidant genes. It has become one of the emerging targets for cancer chemosensitization, and small molecule inhibitors of Nrf2 can enhance the efficacy of chemotherapeutic drugs. Here, we found that flumethasone, a glucocorticoid, inhibited Nrf2 signaling in A549 and H460 cells by promoting Nrf2 protein degradation. Moreover, flumethasone significantly increased the sensitivity of A549 and H460 cells to chemotherapeutic drugs including cisplatin, doxorubicin and 5-FU. In mice bearing A549-shControl cells-derived xenografts, the size and weight of xenografts in the flumethasone and cisplatin combination group had a significant reduction compared with those in the cisplatin group, while in mice bearing A549-shNrf2 cells-derived xenografts, the size and weight of the xenografts in the combination group had no significant difference compared with those in the cisplatin group, demonstrating that chemosensitization effect of flumethasone is Nrf2-dependent. This work suggests that flumethasone can potentially be used as an adjuvant sensitizer to enhance the efficacy of chemotherapeutic drugs in lung cancer.

2.
Redox Biol ; 29: 101390, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31785531

RESUMO

The human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promotes proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.

3.
Molecules ; 24(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795214

RESUMO

Polo-box domain of polo-like kinase 1 (PLK1-PBD) has a pivotal role in cell proliferation and could be implicated as a potential anticancer target. Although some small-molecule inhibitors have been developed, their clinical application has been restricted by the poor selectivity. Therefore, there is an urgent need to develop effective PLK1-PBD inhibitors. Herein, we have developed a virtual screening protocol to find PLK1-PBD inhibitors by using combination of structure-based pharmacophore modeling and molecular docking. This protocol was successfully applied to screen PLK1-PBD inhibitors from specs database. MTT assay indicated that five screened hits suppressed the growth of HeLa cells. Particularly, hit-5, as a selective PLK1 inhibitor targeting PLK1-PBD, significantly inhibited the progression of HeLa cells-derived xenograft, with no obvious side effects. This work demonstrates that hit-5 may be a potential anticancer agent.

4.
Cancers (Basel) ; 11(12)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783584

RESUMO

Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.

5.
Molecules ; 24(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766720

RESUMO

Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 µM). MTT assay confirmed that compounds 1-4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.

6.
Molecules ; 24(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480625

RESUMO

Tubulin inhibitors have been considered as potential drugs for cancer therapy. However, their drug resistance and serious side-effects are the main reasons for clinical treatment failure. Therefore, there is still an urgent need to develop effective therapeutic drugs. Herein, a structure-based pharmacophore model was developed based on the co-crystallized structures of the tubulin with a high resolution. The model including one hydrogen-bond acceptor feature, two aromatic features, and one hydrophobic feature was further validated using the Gunner-Henry score method. Virtual screening was performed by an integrated protocol that combines drug-likeness analysis, pharmacophore mapping, and molecular docking approaches. Finally, five hits were selected for biological evaluation. The results indicated that all these hits at the concentration of 40 µM showed an inhibition of more than 50% against five human tumor cells (MCF-7, U87MG, HCT-116, MDA-MB-231, and HepG2). Particularly, hit 1 effectively inhibited the proliferation of these tumor cells, with inhibition rates of more than 80%. The results of tubulin polymerization and colchicine-site competition assays suggested that hit 1 significantly inhibited tubulin polymerization by binding to the colchicine site. Thus, hit 1 could be used as a potential chemotherapeutic agent for cancer treatment. This work also demonstrated the potential of our screening protocol to identify biologically active compounds.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Relação Quantitativa Estrutura-Atividade , Moduladores de Tubulina/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Humanos , Ligantes , Modelos Moleculares , Polimerização , Tubulina (Proteína)/metabolismo
7.
J Cell Biochem ; 120(10): 17744-17756, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31210372

RESUMO

Absent in melanoma 2 (AIM2) is a critical component in natural immunity system and is closely related to cancer initiation and development. It has been shown that AIM2 inhibited colorectal cancer (CRC) development and cell proliferation. It remains unresolved how AIM2 acts on CRC metastasis. In this study, we assessed migration, invasion ability, and epithelial-mesenchymal transition (EMT) program upon AIM2 overexpression or knockdown in human CRC cells. Transwell assay demonstrated that upregulation of AIM2 reduced cell migration and invasion. Epithelial marker E-cadherin was augmented and mesenchymal markers vimentin, as well as Snail, were examined decreased by Western blot, real-time polymerase chain reaction, and immunofluorescence. Correspondingly, knockdown of AIM2 led to a reverse consequence. In addition, AIM2 regulated Akt phosphorylation and effects of AIM2 on cell invasion and EMT were recovered after administration of Akt inhibitor, suggesting that AIM2 suppressed EMT dependent on Akt pathway. In addition, caspase-1 inhibitor exposure indicated that AIM2 abrogated EMT through the inflammasome pathway as well. In summary, AIM2 suppressed EMT via Akt and inflammasome pathways in human CRC cells.

8.
J Cell Physiol ; 234(11): 20161-20173, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30953357

RESUMO

The human absent in melanoma 2 (AIM2) is considered as a DNA recognizer. AIM2 has been described as a tumor suppressor gene in the early years. But recent studies suggested that it functions as an oncogene in several cancers. However, its roles in non-small-cell lung cancer (NSCLC) remain unclear. Here we reported that AIM2 highly expressed in NSCLC cells and exhibited a tumor-promoting property both in vitro and in vivo. Besides, AIM2 short hairpin RNA (shRNA)-mediated suppression of cell proliferation was triggered by the accumulation of cells at the G2/M phase. Knockdown of AIM2 reduced the inflammasome formation, while overexpression of AIM2 or stimulation by poly(dA:dT) induced the inflammasome formation. Interestingly, blockade of the inflammasome by caspase-1 inhibitor VX-765 or ASC small interfering RNA (siRNA) abolished the effects brought by AIM2 shRNA and AIM2 plasmid. In summary, our results revealed that AIM2 functioned as an oncogene in NSCLC in an inflammasome-dependent way.

9.
Redox Biol ; 22: 101131, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735911

RESUMO

Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.


Assuntos
Desoxicitidina/análogos & derivados , Digoxina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Humanos , Camundongos , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncol Lett ; 15(5): 7981-7986, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29849803

RESUMO

The present study aimed to observe the effects of sulindac sulfide on the proliferation and apoptosis of human breast cancer cells MCF-7, and to explore the potential underlying molecular mechanism. The inhibitory ratio was detected using a cell counting kit-8 assay. The changes in cell cycle distribution were assessed using flow cytometry (FCM). Furthermore, the changes in cell apoptosis rates were detected by Hoechst 33258 staining and FCM coupled with Annexin V-FITC/propidium iodide (PI) staining. In addition, the protein expression was detected using western blotting. Sulindac sulfide was able to inhibit the proliferation of breast cancer in a dose- and time-dependent manner. In addition, sulindac sulfide altered the cell cycle of breast cancer cells. The results of Hoechst 33258 staining and FCM coupled with Annexin V-FITC/PI staining demonstrated that sulindac sulfide could significantly induce the apoptosis of MCF-7 cells in a dose-dependent, and time-dependent manner. The western blot analysis demonstrated the protein expression of Bcl-2 was downregulated, and Bax and cleaved caspase-3 were upregulated. The results of the present study suggest that sulindac sulfide can inhibit the proliferation and induce the apoptosis of MCF-7 cells.

11.
Inflamm Res ; 65(8): 603-12, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27043920

RESUMO

OBJECTIVE: Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has generally been used for the treatment of various allergic diseases. However, there is little information about the anti-inflammatory effects of baicalin for allergic rhinitis. This study aims to investigate the anti-allergic effect of baicalin on allergic response in ovalbumin (OVA)-induced allergic rhinitis guinea pigs and lipopolysaccharide (LPS)-stimulated human mast cells. METHODS: Using in vivo models, we evaluated the effect of baicalin on allergic rhinitis symptoms via recording the number of nasal rubs and sneezes. The levels of histamine, OVA-specific immunoglobulin E(IgE), eosinophil cationic protein (ECP) and inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The histological changes of nasal mucosa were observed by light microscope after HE staining. In vitro, the release of histamine and ß-hexosaminidase of compound 48/80-induced human mast cells were measured by ELISA and PNP-NAG colorimetry, respectively. The productions of inflammatory cytokines of LPS-stimulated human mast cells were determined using ELISA. Western blot was used to test the protein expression of JAK2, p-JAK2, STAT5, p-STAT5, IKKß, p-IKKß, IκBα, p-IκBα and NF-κB (p65) of LPS-stimulated human mast cells. RESULTS: The oral administration of baicalin at doses of 50 and 200 mg/kg improved allergic rhinitis symptoms and the histological changes of nasal mucosa and decreased the serum levels of histamine, ECP, interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α and OVA-specific IgE in OVA-induced allergic rhinitis guinea pigs. In vitro, baicalin suppressed the release of histamine and ß-hexosaminidase in compound 48/80-induced human mast cells. In addition, baicalin also inhibited the productions of inflammatory cytokines such as IL-1ß, IL-6, IL-8 and TNF-α and suppressed the phosphorylation of JAK2, STAT5, IKKß, IκBα and the nuclear translocation of NF-κB (p65) subunit in LPS-stimulated human mast cells. CONCLUSIONS: These results suggest that baicalin can effectively prevent allergic response in OVA-induced allergic rhinitis guinea pigs and inhibit inflammatory response via blocking JAK2-STAT5 and NF-κB signaling pathways in LPS-stimulated human mast cells. Considered together,the results show that baicalin may be a useful drug in the treatment of allergic rhinitis.


Assuntos
Antialérgicos/uso terapêutico , Flavonoides/uso terapêutico , Rinite Alérgica/tratamento farmacológico , Animais , Antialérgicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Flavonoides/farmacologia , Cobaias , Humanos , Imunoglobulina E/sangue , Janus Quinase 2/metabolismo , Lipopolissacarídeos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , NF-kappa B/metabolismo , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Ovalbumina , Rinite Alérgica/sangue , Rinite Alérgica/imunologia , Fator de Transcrição STAT5/metabolismo
12.
Yao Xue Xue Bao ; 50(6): 702-7, 2015 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-26521440

RESUMO

This study is to investigate the inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide(LPS)-stimulated HMC-1 mast cells. The cytotoxicity of kaempferol to HMC-1 mast cells were analyzed by using MTT assay and then the administration concentrations of kaempferol were established. Histamine, IL-6, IL-8, IL-1ß and TNF-α were measured using ELISA assay in activated HMC-1 mast cells after incubation with various concentrations of kaempferol (10, 20 and 40 µmol.L-1). Western blot was used to test the protein expression of p-IKKß, IκBα, p-IκBα and nucleus NF-κB of LPS-induced HMC-1 mast cells after incubation with different concentrations of kaempferol. The optimal concentrations of kaempferol were defined as the range from 5 µmol.L-1 to 40 µmol.L-1. Kaempferol significantly decreased the release of histamine, IL-6, IL-8, IL-1ß and TNF-α of activated HMC-1 mast cells (P<0.01). After incubation with kaempferol, the protein expression of p-IKKß, p-IKBa and nucleus NF-κB (p65) markedly reduced in LPS-stimulated HMC-1 mast cells (P<0.01). Taken together, we concluded that kaempferol markedly inhibit mast cell-mediated inflammatory response. At the same time, kaempferol can inhibit the activation of IKKß, block the phosphorylation of IκBα, prevent NF-KB entering into the nucleus, and then decrease the release of inflammatory mediators.


Assuntos
Inflamação/metabolismo , Quempferóis/farmacologia , Mastócitos/efeitos dos fármacos , Células Cultivadas , Histamina/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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