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1.
Chem Biol Interact ; 312: 108813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494105

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo), a pathway that regulates several physiological and biological features, is involved in RMS tumorigenesis. For instance, an upregulation of the Hpo downstream effector Yes-Associated Protein 1 (YAP) leads to the development of embryonal rhabdomyosarcoma (eRMS) in murine activated muscle satellite cells. On the other hand, the YAP paralog transcriptional co-activator with PDZ-binding motif (TAZ) is overexpressed in alveolar rhabdomyosarcoma (aRMS) patients with poor survival. YAP and TAZ exhibit both cytoplasmic and nuclear functions. In the nucleus, YAP binds TEADs (TEA domain family members) factors and together they constitute a complex that is able either to activate the transcription of several genes such as MYC, Tbx5 and PAX8 or to maintain the stability of others like p73. Due to the key role of YAP and TAZ in cancer, the identification and/or development of new compounds able to block their activity might be an effective antineoplastic strategy. Verteporfin (VP) is a molecule able to stop the formation of YAP/TEAD complex in the nucleus. The aim of this study is to evaluate the action of VP on RMS cell lines. This work shows that VP has an anti-proliferative activity on all RMS cell lines analyzed. Depending on RMS cell lines, VP affects cell cycle differently. Moreover, VP is able to decrease YAP protein levels, and to induce the activation of apoptosis mechanism through the cleavage of PARP-1. In addition, Annexin V assay showed the activation of apoptosis and necrosis after VP treatment. In summary, the ability of VP to disrupt RMS cell proliferation could be a novel and valuable strategy to improve the therapeutic approaches in treating rhabdomyosarcoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Verteporfina/farmacologia , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Fatores de Transcrição/metabolismo
2.
Chem Biol Interact ; 311: 108789, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401089

RESUMO

The cytotoxicity of a dinuclear imine-copper (II) complex 2, and its analogous mononuclear complex 1, toward different melanoma cells, particularly human SKMEL-05 and SKMEL-147, was investigated. Complex 2, a tyrosinase mimic, showed much higher activity in comparison to complex 1, and its reactivity was verified to be remarkably activated by UVB-light, while the mononuclear compound showed a small or negligible effect. Further, a significant dependence on the melanin content in the tumor cells, both from intrinsic pigmentation or stimulated by irradiation, was observed in the case of complex 2. Similar tests with keratinocytes and melanocytes indicated a much lower sensitivity to both copper (II) complexes, even after exposition to UV light. Clonogenic assays attested that the fractions of melanoma cells survival were much lower under treatment with complex 2 compared to complex 1, both with or without previous irradiation of the cells. The process also involves generation of reactive oxygen species (ROS), as verified by EPR spectroscopy, and by using fluorescence indicators. Autophagic assays indicated a remarkable formation of cytoplasmic vacuoles in melanomas treated with complex 2, while this effect was not observed in similar treatment with complex 1. Monitoring of specific protein LC3 corroborated the simultaneous occurrence of autophagy. A balance interplay between different modes of cell death, apoptosis and autophagy, occurs when melanomas were treated with the dinuclear complex 2, in contrast to the mononuclear complex 1. These results pointed out to different mechanisms of action of such complexes, depending on its nuclearity.


Assuntos
Complexos de Coordenação/química , Cobre/química , Iminas/química , Monofenol Mono-Oxigenase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Humanos , Melaninas/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/metabolismo , Raios Ultravioleta
3.
Chem Biodivers ; 16(8): e1900325, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31290253

RESUMO

Chronic myeloid leukemia (CML) is a lethal malignancy, and the progress toward long-term survival has stagnated in recent decades. Pristimerin, a quinone methide triterpenoid isolated from the Celastraceae and Hippocrateaceae families, is well-known to exert potential anticancer activities. In this study, we investigated the effects and the mechanisms of action on CML. We found that pristimerin inhibited cell proliferation of K562 CML cells by causing G1 phase arrest. Furthermore, we demonstrated that pristimerin triggered autophagy and apoptosis. Intriguingly, pristimerin-induced cell death was restored by an autophagy inhibitor, suggesting that autophagy is cross-linked with pristimerin-induced apoptosis. Further studies revealed that pristimerin could produce excessive reactive oxygen species (ROS), which then induce JNK activation. These findings provide clear evidence that pristimerin might be clinical benefit to patients with CML.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células K562 , Espécies Reativas de Oxigênio/metabolismo , Triterpenos/química
4.
Chem Biol Interact ; 311: 108749, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31325423

RESUMO

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.


Assuntos
Ácido Glicirretínico/análogos & derivados , Hipertensão Pulmonar/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina/toxicidade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/uso terapêutico , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Eur J Med Chem ; 178: 116-130, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31177073

RESUMO

In this study, a series of novel HDAC inhibitors, using 1,2,4-oxadiazole-containing as the cap group, were synthesized and evaluated in vitro. Compound 14b, N-hydroxy-2-(methyl((3-(1-(4-methylbenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)amino)pyrimidine-5-carboxamide, displayed the most potent histone deacetylase (HDAC) inhibition, especially against HDAC1, 2, and 3 with IC50 values of 1.8, 3.6 and 3.0 nM, respectively. In vitro antiproliferative studies confirmed that 14b was more potent than SAHA, with IC50 values against 12 types of cancer cell lines ranging from 9.8 to 44.9 nM. The results of Western blot assays showed that compound 14b can significantly up-regulate the acetylation of the biomarker his-H3 and molecular docking analyses revealed the mode of action of compound 14b against HDAC1. The results of flow-cytometry analysis suggested that compound 14b induces cell cycle arrest at the G1 phase and has apoptotic effects. Further investigation of the activity of 14b on the primary cells of three patients, showed IC50 values of 21.3, 61.1, and 77.4 nM. More importantly, an oral bioavailability of up to 53.52% was observed for 14b. An in vivo pharmacodynamic evaluation demonstrated that compound 14b can significantly inhibit tumor growth in a Daudi Burkitt's lymphoma xenograft model, with tumor inhibition rates of 53.8 and 46.1% observed at 20 and 10 mg/kg when administered p.o. and i.v., respectively. These results indicate that compound 14b may be a suitable lead for further evaluation and development as an HDAC inhibitor and a potent anticancer agent.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Oxidiazóis/uso terapêutico , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histona Desacetilase 1/química , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Food Chem Toxicol ; 131: 110533, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150783

RESUMO

Hepatocellular carcinoma is the fifth most common and the third most lethal cancer worldwide. In recent years, natural flavonoids have drawn great attention as repository for the exploitation of novel antineoplastic agents. 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a functional chalcone isolated from the buds of Cleistocalyx operculatus, has been reported to exert potent cytotoxicity against multi-drug resistant BEL-7402/5-FU cells. In this study, the precise mechanisms of DMC-mediated growth inhibition in BEL-7402/5-FU cells were further investigated. DMC was found to trigger apoptosis predominantly via the mitochondria-dependent pathway and the enhancement of reactive oxygen species (ROS) generation. Meanwhile, DMC induced G1 cell cycle arrest through downregulation of cyclin D1 and CDK4. Furthermore, DMC increased p53 level and inhibited NF-κB nuclear-localization via suppression of PI3K/AKT signaling axis, which might be the underlying mechanism of DMC-induced apoptosis and cell cycle arrest in BEL-7402/5-FU cells. Collectively, the study elucidated the mechanisms by which DMC may inhibit the growth of BEL-7402/5-FU cells and suggested the possibility that DMC might be a promising candidate therapeutic agent for hepatoma treatment in the future.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Flores/química , Humanos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Syzygium/química , Proteína Supressora de Tumor p53/metabolismo
7.
Chem Biol Interact ; 309: 108703, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194954

RESUMO

ß-2-himachalen-6-ol (HC), a major sesquiterpene isolated from the Lebanese wild carrot umbels, was shown to possess remarkable in vitro and in vivo anticancer activities. The present study investigates the anti-metastatic activity of HC post 4T1 breast cancer cells inoculation in a murine model. The effect of HC on 4T1 cell viability was assessed using WST-1 kit, while cell cycle analysis was performed using flow cytometry. Tumor development and metastasis were evaluated by injecting 4T1 cells in the mice mammary gland region followed by either HC or cisplatin treatment. The 6-thioguanine assay was used for the quantification of metastatic cells in the blood. HC treatment caused a dose-dependent decrease in cell viability with IC50 and IC90 values of 7 and 28 µg/mL respectively. Concomitant treatment with cisplatin significantly reduced cell viability when compared to cells treated with cisplatin or HC alone. Flow cytometry revealed a significant increase (p˂0.05) in cell count in the Sub-G1 phase at HC 10 µg/mL, and total DNA fragmentation (p˂0.001) at HC 25 µg/mL. Annexin/PI staining showed early and late apoptotic mode of cell death upon treatment with HC. Histopathological evaluation revealed less incidence of primary and metastatic tumor/inflammation in the HC and cisplatin treated groups. Tumor size and colony-forming units were significantly decreased in the HC treated group. HC treatment induced cell cycle arrest, promoted apoptosis and reduced the incidence of primary and metastatic lesions caused by 4T1 cells. The present findings suggest that HC has an anti-metastatic potential against aggressive types of cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Sesquiterpenos/uso terapêutico , Pele/patologia , Transplante Homólogo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
8.
Am J Chin Med ; 47(4): 841-863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096772

RESUMO

Fisetin, a naturally occurring flavonoid, is found in common fruits and vegetables and has been shown to induce cytotoxic effects in many human cancer cell lines. No information has shown that fisetin induced cell cycle arrest and apoptosis in mouse leukemia WEHI-3 cells. We found that fisetin decreased total viable cells through G0/G1 phase arrest and induced sub-G1 phase (apoptosis). We have confirmed fisetin induced cell apoptosis by the formation of DNA fragmentation and induction of apoptotic cell death. Results indicated that fisetin induced intracellular Ca 2+ increase but decreased the ROS production and the levels of ΔΨ m in WEHI-3 cells. Fisetin increased the activities of caspase-3, -8 and -9. Cells were pre-treated with inhibitors of caspase-3, -8 and -9 and then treated with fisetin and results showed increased viable cell number when compared to fisetin treated only. Fisetin reduced expressions of cdc25a but increased p-p53, Chk1, p21 and p27 that may lead to G0/G1 phase arrest. Fisetin inhibited anti-apoptotic protein Bcl-2 and Bcl-xL and increased pro-apoptotic protein Bax and Bak. Furthermore, fisetin increased the protein expression of cytochrome c and AIF. Fisetin decreased cell number through G0/G1 phase arrest via the inhibition of cdc25c and induction of apoptosis through caspase-dependent and mitochondria-dependent pathways. Therefore, fisetin may be useful as a potential therapeutic agent for leukemia.


Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Flavonoides/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Leucemia/genética , Leucemia/patologia , Animais , Camundongos , Células Tumorais Cultivadas
9.
Mol Med Rep ; 19(6): 5417-5423, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059053

RESUMO

Hepatocellular carcinoma (HCC) has become a global public health problem. Therefore, the development of novel and effective therapeutic agents for the treatment of HCC is considered an emergency. Avicularin, a bio­active flavonoid from plants, has been reported to exhibit diverse pharmacological properties. The aim of the present study was to investigate the role of avicularin in HCC and the underlying mechanism of action. Huh7 cells were treated with avicularin in a concentration­dependent manner, and the cell proliferation was examined using a 3­(4, 5­dimethylthiazol­2­yl)­2, 5­diphenyltetrazolium bromide assay kit. The cell migration and invasion abilities were detected using wounding­healing assays and Transwell assays. Flow cytometric analysis was performed to investigate the cell cycle distribution and cell apoptosis. The activity of nuclear factor (NF)­κB (p65), cyclooxygenase­2 (COX­2) and peroxisome proliferator­activated receptor γ (PPAR­Î³) were measured by reverse transcription­quantitative polymerase chain reaction and western blot analyses, respectively. The results indicated that avicularin treatment markedly decreased cell proliferation concentration­dependently in HCC, and inhibited cell migration and invasion in Huh7 cells. It was also found that the treatment of avicularin markedly inhibited the G0/G1­phase cells and decreased the accumulation of S­phase cells in the cell cycle and induced cell apoptosis. In addition, it was confirmed that the anticancer efficacy of avicularin in HCC was dependent on the regulation of NF­κB (p65), COX­2 and PPAR­Î³ activities. In conclusion, the findings suggested that avicularin serves an antineoplastic role in HCC and may provide a potential therapeutic strategy for the treatment of HCC.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , PPAR gama/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/genética , PPAR gama/genética
10.
Chem Biol Interact ; 308: 1-10, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071337

RESUMO

Diarylheptanoids display an array of biological and pharmacological properties. We previously reported the synthesis of a diarylheptanoid Alpinoid c and a series of its derivatives, evaluated their cytotoxicity against various human cancer cells. We found some of these derivatives were significantly more potent than Alpinoid c in preventing the proliferation of various cancer cell lines. Among these, (S, E)-1-(3, 4 dimethoxyphenyl)-6-hydroxy-7-phenylhept-4-en-3-one (DPHP) showed most potent cytotoxicity against COLO205 cells, however, the mechanism by which DPHP prevents the growth of these colon cancer cells remains unknown. In the current study, we investigated the molecular mechanism of DPHP on colon cancer cells. DPHP inhibited the proliferation of COLO205 (IC50 7.01 ±â€¯0.62 µM) and A549 (IC50 20.03 ±â€¯3.11 µM) cells more specifically than normal human colon epithelial cell line NCM460 (IC50 55.6 ±â€¯4.02 µM). In COLO205 cells, DPHP induced cell shrinkage, membrane blebbing, chromatin condensation, phosphatidylserine externalization, and an accumulation of cells at sub-G1 phase. Further analysis these cells treated with DPHP revealed a decrease in mitochondrial membrane potential, an increase in Bax/Bcl2 ratio, the release of cytochrome c, activation of caspases -9, -3/7, and cleavage of the poly-ADP-ribose polymerase. DPHP treatment resulted in inhibition of hypoxia induced VEGF downstream signaling pathway in COLO205 cells is concurrent with inhibition of angiogenesis in CAM. Based on these data we suggest that DPHP significantly induced apoptosis possibly via intrinsic mitochondrial apoptosis pathway and inhibited angiogenesis. Our study suggests DPHP could be a therapeutic agent in treating colon cancer.


Assuntos
Apoptose/efeitos dos fármacos , Diarileptanoides/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Células A549 , Animais , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Embrião de Galinha , Diarileptanoides/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
11.
Eur J Med Chem ; 176: 61-67, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096119

RESUMO

The present study was designed to synthesize and evaluate ursolic acid hybrid compounds against glioma cells. Initial screening revealed that most of the synthesized compounds displayed better inhibitory effect on glioma cell proliferation compared to parent ursolic acid. The mechanism of inhibitory effect of the most potent compound 6d on glioma cells was investigated in detail. Treatment with compound 6d significantly (p < 0.001) reduced U251 and C6 cell proliferation at 48 h. The growth of U251 and C6 glioma cells was reduced to minimum level (17 and 21%) on treatment with 10 µM concentration of compound 6d. Treatment of the U251 cells with 10 µM concentration of compound 6d caused a significant (p < 0.05) inhibition of cAMP level. In U251 cell cultures treatment with compound 6d at 10 µM concentration enhanced proportion of apoptotic cells to 69.32% compared to 2.34% in the control cultures. The compound 6d treatment of U251 cells for 48 h caused arrest of cell cycle in the G0/G1 phase with consequent decrease of cell population in G2/M and S phases. The results from TEM showed that compound 6d treatment of U251 cells for 48 h caused blebbing of the cell membranes, chromatin condensation, appearance of foamy cytoplasmic material and autophagic vacuoles. The results from SEM revealed that compound 6d treatment of U251 cells caused a marked inhibition of microvilli and extensions on the cell surfaces. Thus present study demonstrates that compound 6d inhibits glioma cell growth, induces apoptosis and arrest cell cycle through metabolic pathway down-regulation. Therefore, compound 6d can be evaluated further for the treatment of glioma.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , AMP Cíclico/metabolismo , Glioma/tratamento farmacológico , Triterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Ratos , Transdução de Sinais/efeitos dos fármacos , Triterpenos/síntese química
12.
Eur J Med Chem ; 176: 175-186, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103898

RESUMO

The development of optically pure drugs is the trend of new drugs research. Searching for optically pure metallodrugs against cancer has not been taken seriously. [CuL4Cl]Cl·2CH2Cl2·H2O (1) and [CuL4Br]Br·2CH2Cl2 (2) (L = 2-amino-5-dehydroabietyl-1,3,4-thiadiazole), two rosin-derivative based optically pure chiral copper(II) complexes, are rationally synthesized as potential anticancer agents. 1 exhibits effective in vitro and in vivo anticancer activities and tolerable toxicities. 1 promotes MCF-7 cell death by combination of cell arrest at G1 phase, apoptosis (both extrinsic and intrinsic apoptotic pathways), anti-metastasis, anti-angiogenesis, damage of DNA, protein and lipid, and autophagy mediated by the oxidative stress which is confirmed by ROS generation and intracellular glutathione depletion assays. 1 can be identified as a lead anticancer molecule of therapeutic importance. This work may offer insights into the design and mechanism study of multifunctional optically pure metal-based anticancer candidates derived from natural products.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Cobre/química , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estereoisomerismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Med Chem ; 176: 117-128, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108261

RESUMO

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 µM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 µM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Oximas/farmacologia , Xantinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/química , Oximas/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Xantinas/síntese química , Xantinas/química , Xantinas/toxicidade , Proteína X Associada a bcl-2/metabolismo
14.
J Med Food ; 22(5): 444-450, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084542

RESUMO

Studies have identified the potential of chemopreventive effects of sulforaphane (SFN); however, the underlying mechanisms of its effect on breast cancer require further elucidation. This study investigated the anticancer effects of SFN that specifically induces G1/S arrest in breast ductal carcinoma (ZR-75-1) cells. The proliferation of the cancer cells after treatment with SFN was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA content and cell cycle status were analyzed through flow cytometry. Our results demonstrated the inhibition of growth in ZR-75-1 cells upon SFN exposure. In addition, SERTAD1 (SEI-1) caused the accumulation of SFN-treated G1/S-phase cells. The downregulation of SEI-1, cyclin D2, and histone deacetylase 3 suggested that in addition to the identified effects of SFN against breast cancer prevention, it may also exert antitumor activities in established breast cancer cells. In conclusion, SFN can inhibit growth of and induce cell cycle arrest in cancer cells, suggesting its potential role as an anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Proteínas Nucleares/genética , Transativadores/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D2/genética , Ciclina D2/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transativadores/metabolismo , Verduras/química
15.
Chem Biol Interact ; 307: 105-115, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31054283

RESUMO

Neutral endopeptidase (NEP) is an enzyme implicated in development of different tumors, e.g. colorectal cancer (CRC). In this study, the anti-cancer effects of NEP inhibitors, thiorphan (synthetic compound) and sialorphin (naturally occurring pentapeptide) on CRC cells were investigated. Moreover, we synthesized some derivatives of sialorphin (alanine scan analogues: AHNPR, QANPR, QHAPR, QHNAR; N-acetylated sialorphin; C-amidated sialorphin, and C-amidated alanine scan analogues) to examine the biological activity of these inhibitors on CRC cells. The cytotoxic activity of the NEP inhibitors against CRC cell lines (SW620 and LS180) and normal human fibroblasts (HSF) was evaluated. Additionally, the influence of NEP inhibitors on proliferation, cell cycle progression, induction of apoptosis, and the level of phosphorylation of MAP kinases and mTORC1 signaling pathway proteins in CRC cells were examined. The NEP inhibitors were non-cytotoxic to HSF cells; however, most of them slightly decreased the viability and inhibited proliferation of CRC cells. The N-acetylation or C-amidation of sialorphin or its alanine scan analogues resulted in decreased or abolished anti-proliferative activity of the NEP inhibitors towards the CRC cells. Additionally, thiorphan and sialorphin enhanced the anti-proliferative activity of other CRC-cell growth inhibitors (atrial natriuretic peptide-ANP and melphalan-MEL). The mechanisms involved in the anti-proliferative effects of the tested inhibitors were mediated via NEP and associated with induction of cell cycle arrest in the G0/G1 phase, increased activity of ERK1/2, and a reduced level of phosphorylation of mTOR (Ser2448), 4E-BP1, and p70S6K. However, the NEP inhibitors did not induce apoptosis in the CRC cells. These results have indicated that thiorphan and sialorphin or its derivatives AHNPR, QANPR, QHAPR, and QHNAR have the potential to be used as agents in treatment of patients with CRC.


Assuntos
Proliferação de Células/efeitos dos fármacos , Endopeptidases/metabolismo , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Tiorfano/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Endopeptidases/química , Endopeptidases/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Peptídeos/síntese química , Peptídeos/química , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteases/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tiorfano/química
16.
Eur J Med Chem ; 174: 265-276, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051401

RESUMO

On the basis of the hybridization strategy of natural products, a total of 32 novel celastrol hybrids were designed, synthesized and evaluated for their antitumor activities. Most of these derivatives exihibited significant antiproliferative activities compared to celastrol, among which compound 29 displayed the strongest inhibitory capability [IC50 = 0.15 ±â€¯0.03 µM (A549),0.17 ±â€¯0.03 µM (MCF-7), 0.26 ±â€¯0.02 µM (HepG2)], which exhibited equal or superior anti-cancer activities in comparison to 2-cyano-3,12-dioxoolean-1,9 (11)-dien-28-oic acid methyl ester (CDDO-Me). The mechanism of pharmacological research indicated that 29 possessed the ability to disrupt Hsp90-Cdc37 complex which was stronger than celastrol. Meanwhile, compound 29 could induce abnormal regulation of clients (p-Akt and Cdk4) of Hsp90 and cell cycle arrest at G0/G1 phase in a concentration-dependent manner. In addition, compound 29 could also induce cell apoptosis through the death receptor pathway on A549 cells. Taken together, our results demonstrated that 29 might be a promising novel candidate for further druggability research.


Assuntos
Antineoplásicos/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Chaperoninas/metabolismo , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química
17.
J BUON ; 24(1): 285-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941982

RESUMO

PURPOSE: The purpose of the present study was to investigate the anticancer properties of isoacteoside against OVCAR-3 human ovarian cancer cells. Its effects on apoptosis, reactive oxygen species (ROS) generation, cell invasion, cell cycle arrest and its effects on tumor volume and weight were also evaluated in the current study. METHODS: MTT assay was used to study the cytotoxic effects of the compound on the cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and matrigel assay were carried out to study the effects of isoacteoside on cell migration and cell invasion respectively. Non-cancer ovarian cell line SV-40 served as control. RESULTS: Isoacteoside exerted both dose-dependent as well as time-dependent growth inhibitory effects on ovarian cancer cells with IC50 values of 15 µM at 24h incubation. Isoacteoside led to early and late apoptosis induction in these cells. Isoacteoside also led to sub-G1 cell cycle arrest which showed strong dose-dependence. Isoacteoside treatment also led to inhibition of cell migration and cell invasion. The results revealed that OVCAR-3 tumor growth was significantly suppressed by isoacteoside administration, compared with that in the control group. At the end of the 5-week period of isoacteoside treatment, the average tumor growth and volume in the untreated control group were considerably higher than those in the treated groups. CONCLUSION: In brief, the current study indicates that isoacteoside has a great potential in suppressing both in vitro and in vivo ovarian cancer cell growth and can be used as a possible anticancer agent.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glucosídeos/farmacologia , Neoplasias Ovarianas/prevenção & controle , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Oncol ; 54(4): 1481-1495, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968156

RESUMO

Melanoma represents a significant challenge in cancer treatment due to the high drug resistance of melanomas and the patient mortality rate. This study presents data indicating that nanomolar concentrations of the hormonally active form of vitamin D, 1α,25­dihydroxyvitamin D3 [1α,25(OH)2D3], its non­calcemic analogues 20S­hydroxyvitamin D3 and 21­hydroxypregnacalciferol, as well as the low­calcemic synthetic analog calcipotriol, modulate the efficacy of the anticancer drugs cisplatin and dacarbazine. It was observed that vitamin D analogs sensitized melanoma A375 cells to hydrogen peroxide used as an inducer of oxidative stress. On the other hand, only 1α,25(OH)2D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 µM) exhibited a higher overall antiproliferative activity than dacarbazine. Cisplatin treatment of melanoma cells resulted in an induction of apoptosis as demonstrated by flow cytometry (accumulation of cells at the subG1 phase of the cell cycle), whereas dacarbazine caused G1/G0 cell cycle arrest, with the effects being improved by pre­treatment with vitamin D analogs. Treatment with cisplatin resulted in an initial increase in the level of reactive oxygen species (ROS). Dacarbazine caused transient stimulation of ROS levels and the mitochondrial membrane potential (Δψm) (after 1 or 3 h of treatment, respectively), but the effect was not detectable following prolonged (24 h) incubation with the drug. Vitamin D exhibited modulatory effects on the cells treated with dacarbazine, decreasing the half maximal inhibitory concentration (IC50) for the drug, stimulating G1/G0 arrest and causing a marked decrease in Δψm. Finally, cisplatin, dacarbazine and 1α,25(OH)2D3 displayed modulatory effects on the expression of ROS and vitamin D­associated genes in the melanoma A375 cells. In conclusion, nanomolar concentrations of 1,25(OH)2D3 only had minor effects on the proliferation of melanoma cells treated with dacarbazine, decreasing the relative IC50 value. However, co­treatment with vitamin D analogs resulted in the modulation of cell cycle and ROS responses, and affected gene expression, suggesting possible crosstalk between the signaling pathways of vitamin D and the anticancer drugs used in this study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Sinergismo Farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Melanoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/patologia , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Vitamina D/uso terapêutico
19.
Eur J Pharmacol ; 853: 184-192, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928629

RESUMO

Celastrol exhibits anticancer activity and has a number of potential molecular targets. Among them, the proteasome has attracted particular attention. Although celastrol inhibits multiple myeloma (MM) cell proliferation, the induction of proteasome-inhibitory activity by celastrol in MM cells at the cellular level and in tumors of mice bearing xenografts has not been confirmed. In the present study, we found that celastrol inhibited the caspase-like (ß1), trypsin-like (ß2) and chymotrypsin-like (ß5) proteasome activities of purified human 20S proteasomes, with half-maximal inhibitory concentration (IC50) values of 7.1, 6.3, and 9.3 µmol/L, respectively. Celastrol also inhibited human MM cellular ß1, ß2, and ß5 proteasome activities, with IC50 values of 2.3, 2.1, and 0.9 µmol/L, respectively. After MM cells were treated with celastrol, a population of apoptotic cells and a population of cells in G0/G1 were observed. Celastrol also inhibited proteasome activity and induced apoptosis in tumor tissue. Treatment of MM.1S and RPMI 8226 tumor-bearing severe combined immunodeficiency (SCID) mice with celastrol reduced the tumor volume. In conclusion, our results reveal the effects of celastrol on proteasome activity in MM cells and shed light on the underlying mechanisms of its anticancer activity, providing a basis for developing celastrol as a potential therapeutic agent for MM.


Assuntos
Apoptose/efeitos dos fármacos , Mieloma Múltiplo/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J BUON ; 24(1): 323-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941988

RESUMO

PURPOSE: Oral cancer is one of the prevalent types of cancer and has been reported to responsible for significant mortality and morbidity. Since treatment options for oral cancer are limited, there is need to explore novel molecules for treatment of oral cancer. In the current study we evaluated the anticancer activity of a plant derived monoterpene, Linalool against oral cancer cell line, OECM-1. METHODS: Cell viability was determined by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining. Cell cycle analysis was carried out by flow cytometry. Cell migration was assessed by wound healing assay and the expression of the proteins was determined by western blotting. RESULTS: The results showed that Linalool inhibited the viability of oral cancer OECM-1 cells in a concentration-dependent manner. The IC50 of Linalool against OECM-1 oral cancer cells was 10 µM as compared to its IC50 of 65 µM against non-cancer FR-2 cells. The anticancer effects were due to the induction of the apoptosis and sub-G1 cell cycle arrest. The results of annexin V/PI further revealed that the apoptotic cell populations increased from 2.6% in the control to 61.3% at 20 µM concentrations. It was observed that Linalool decreased the expression of p-PI3K and p-AKT in a concentration-dependent manner. However, the expression of PI3K and AKT remained almost unaltered. CONCLUSIONS: Taken together it was shown that Linalool monoterpene exerted significant anticancer effects in OECM-1 human oral cancer cells via inducing cell cycle arrest, loss of mitochondrial membrane potential (MMP) and suppressing PI3K/AKT signalling pathway.


Assuntos
Potencial da Membrana Mitocondrial/efeitos dos fármacos , Monoterpenos/farmacologia , Neoplasias Bucais/tratamento farmacológico , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
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