Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nutrients ; 13(9)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34578877

RESUMO

Background: Increasing evidence suggests that combinations of phytochemicals are more efficient than single components in the modulation of signaling pathways involved in cancer development. In this study, the impact of phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol, (X), and resveratrol (RES) and their combinations on the activation and expression of Nrf2 and NF-κB in human hepatocytes and HCC cells were evaluated. Methods: THLE-2 and HepG2 cells were exposed to single phytochemicals and their combinations for 24 h. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cells survival were assessed. The tumor burden was evaluated in mice carrying xenografts. Results: All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells. The increased expression of NQO1 (~90%) was associated with increased ROS generation. X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression. In contrast to single phytochemicals, X + PEITC induced apoptosis. Moderate reduction of tumor burden in mice carrying xenografts following X and PEITC or their combination was observed. Conclusions: Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.

2.
Eur J Pharm Sci ; 166: 105961, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34363938

RESUMO

Novel therapeutics are required to improve treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients. Histone lysine demethylases (KDM) have emerged recently as new potential drug targets for HNSCC therapy. They might also potentiate the action of the inhibitors of EGFR and PI3K signaling pathways. This study aimed at evaluating the anti-cancer effects of KDM4 (ML324) and KDM6 (GSK-J4) inhibitors and their combinations with EGFR (erlotinib) and PI3K (HS-173) inhibitors in HNSCC cells. The effect of the inhibitors on the viability of CAL27 and FaDu cells was evaluated using resazurin assay. The effect of the chemicals on cell cycle and apoptosis was assessed using propidium iodide and Annexin V staining, respectively. The effect of the compounds on gene expression was determined using qPCR and Western blot. The changes in cell cycle distribution upon treatment with the compounds were small to moderate, with the exception of erlotinib, which induced G1 arrest. However, all the compounds and their combinations induced apoptosis in both cell lines. These effects were associated with changes in the level of expression of CDKN1A, CCND1 and BIRC5. The inhibition of KDM4 and KDM6 using ML324 and GSK-J4, respectively, can be regarded as a novel therapeutic strategy in HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Histona Desmetilases , Apoptose , Linhagem Celular Tumoral , Cloridrato de Erlotinib/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases , Piridinas , Sulfonamidas
3.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443375

RESUMO

The study aimed to evaluate the possible modulation of Nrf2, NF-ĸB and STAT3 signaling pathways in the colorectal cancer (CRC) cells line DLD-1 and HCT116 by secondary metabolites of lichens. An attempt was made to indicate the most promising targets in these signaling pathways. Attention was also paid to the effects of the compounds tested on CRC cells using anakoinosis-that is, simultaneous analysis of several signaling pathways. The effects of the tested natural compounds on the activity of selected transcriptional factors related to CRC were analyzed by Western blot and RT-PCR assays. The highest activity against CRC cells was shown by physodic and salazinic acids from the studied secondary metabolites of lichens. As a result, an increase in the activation of transcription factor Nrf2 and the expression of its selected target genes was observed. Physodic and salazinic acids induced the opposite effect in relation to the NF-κB and STAT3 pathways. These results confirmed our earlier observations that lichen-derived compounds have the ability to modulate signaling pathway networks. While caperatic acid affected Wnt/ß-catenin to the most extent, salazinic acid was the most potent modulator of Nrf2, NF-κB and STAT3 pathways. Physodic acid seemed to affect all the investigated pathways.


Assuntos
Neoplasias Colorretais/metabolismo , Depsídeos/farmacologia , Lactonas/farmacologia , Líquens/química , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Depsídeos/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactonas/química , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Metabolismo Secundário/efeitos dos fármacos
4.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443544

RESUMO

Naturally occurring pentacyclic triterpenoid oleanolic acid (OA) serves as a good scaffold for additional modifications to achieve synthetic derivatives. Therefore, a large number of triterpenoids have been synthetically modified in order to increase their bioactivity and their protective or therapeutic effects. Moreover, attempts were performed to conjugate synthetic triterpenoids with non-steroidal anti-inflammatory drugs (NSAIDs) or other functional groups. Among hundreds of synthesized triterpenoids, still the most promising is 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which reached clinical trials level of investigations. The new group of synthetic triterpenoids are OA oximes. The most active among them is 3-hydroxyiminoolean-12-en-28-oic acid morpholide, which additionally improves the anti-cancer activity of standard NSAIDs. While targeting the Nrf2 and NF-κB signaling pathways is the main mechanism of synthetic OA derivatives' anti-inflammatory and anti-cancer activity, most of these compounds exhibit multifunctional activity, and affect cross-talk within the cellular signaling network. This short review updates the earlier data and describes the new OA derivatives and their conjugates in the context of modification of signaling pathways involved in inflammation and cell survival and subsequently in cancer development.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Ácido Oleanólico/farmacologia , Animais , Humanos , Simulação de Acoplamento Molecular , Ácido Oleanólico/química , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
5.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360990

RESUMO

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor-kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
6.
Pharmaceuticals (Basel) ; 14(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34358114

RESUMO

Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling pathways. This study focused on the synthesis and biological evaluation of four diclofenac (DCL)-OAO derivative conjugates in the context of these pathways' modification and hepatic cells survival. Treatment with the conjugates 4d, 3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide, and 4c, 3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester significantly reduced cell viability in comparison to the DCL alone. In THLE-2, immortalized normal hepatocytes treated with these conjugates resulted in the activation of Nrf2 and increased expression in SOD-1 and NQO1, while the opposite effect was observed in the HepG2 hepatoma cells. In both cell lines, reduced activation of the NF-κB and COX-2 expression was observed. In HepG2 cells, conjugates increased ROS production resulting from a reduced antioxidant defense, induced apoptosis, and inhibited cell proliferation. In addition, the OAO morpholide derivative and its DCL hybrid reduced the tumor volume in mice bearing xenografts. In conclusion, our study demonstrated that conjugating diclofenac with the OAO morpholide and a benzyl ester might enhance its anti-cancer activity in HCC.

7.
Nutr Cancer ; : 1-16, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34120541

RESUMO

Cancer prevention particularly related to aging can be improved by the use of phytochemicals combinations. In this study, we evaluated the effect of phenethyl isothiocyanate (PEITC), xanthohumol (XAN), indole-3-carbinol (I3C), and resveratrol (RES) and their combinations on the Nrf2 signaling pathway. Human pancreatic cancer cells MIA-Pa-Ca-2 were treated with the phytochemicals alone or their equimolar mixture for 24 h and activation of Nrf2 and expression of its target genes were evaluated. Phytochemicals alone enhanced Nrf2 activation and expression, but their combinations were more efficient. The mixture of XAN and PEITC was found to be the most potent modulator of the Nrf2 pathway. Moreover, increased levels of P-Nrf2 and P-JNK and decreased level of P-GSK-3ß suggested possible activation of Nrf2 through modulation of these kinases. The combinations of XAN with PEITC and RES with PEITC increased mostly the expression of SOD, GSTP, CAT, and GPx. XAN and PEITC mixture induced the cell cycle arrest in G0/G1 phase and increased apoptotic and autophagy markers. These results indicate that combinations of phytochemicals resembling that occurring in natural diets may efficiently modulate the signaling pathways, which proper function is important for pancreatic cancer prophylaxis or improving the results of conventional therapy.

8.
BMC Cancer ; 21(1): 493, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941107

RESUMO

BACKGROUND: Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/ß-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/ß-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. METHODS: Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of ß-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. RESULTS: Wnt/ß-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. CONCLUSIONS: Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.


Assuntos
Neoplasias Encefálicas/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Glioblastoma/metabolismo , Proteínas de Neoplasias/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Idoso , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Metilases de Modificação do DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Etoricoxib/farmacologia , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Isoxazóis/farmacologia , Lactonas/farmacologia , Masculino , Metilação , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Receptores de Prostaglandina E Subtipo EP4/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Sulfonas/farmacologia , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , beta Catenina/efeitos dos fármacos , beta Catenina/metabolismo
9.
Mol Cell Biochem ; 476(6): 2539-2549, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33635505

RESUMO

Naturally occurring phytochemicals of different origin and structure, arctigenin, bergenin, usnic acid and xanthohumol, were shown to affect Nrf2 pathway in the context of various diseases, but their effect on this pathway in cancer cells was not extensively investigated. This study aimed to evaluate the effect of these compounds on Nrf2 expression and activation in hypopharyngeal FaDu squamous cell carcinoma cells. FaDu cells were treated with 2 or 10 µM arctigenin, bergenin, (+)-usnic acid or xanthohumol for 24 h. While arctigenin, bergenin, and xanthohumol did not affect either Nrf2 expression or activation, (+)-usnic acid treatment increased its transcript level and increased the nuclear/cytosol Nrf2 protein ratio-the measure of Nrf2 pathway activation. Consequently, (+)-usnic acid enhanced the transcription and translation of Nrf2 target genes: NQO1, SOD, and to a lesser extent, GSTP. The treatment of FaDu cells with (+)-usnic acid decreased both GSK-3ß transcript and protein level, indicating its possible involvement in Nrf2 activation. All the tested compounds decreased Bax mRNA but did not change the level of Bax protein. (+)-Usnic acid tended to increase the percentage of early apoptotic cells and LC3 protein, autophagy marker. Significant induction of p53 also was observed after treatment with (+)-usnic acid. In summary, the results of this study indicate that low concentrations of (+)-usnic acid activate Nrf2 transcription factor, most probably as a result of ROS accumulation, but do not lead to FaDu hypopharyngeal carcinoma cells death.


Assuntos
Elementos de Resposta Antioxidante , Benzofuranos/farmacologia , Neoplasias Hipofaríngeas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/patologia , Fator 2 Relacionado a NF-E2/genética , Proteínas de Neoplasias/genética , Transdução de Sinais/genética
10.
Adv Med Sci ; 66(1): 6-20, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33238230

RESUMO

PURPOSE: Glioblastoma is the most common and the deadliest brain cancer. The aim of this study was to analyze the impact of resveratrol and its five analogs: 3,4,4'-trimethoxy, 3,4,2'-trimethoxy, 3,4,2',4'-tetramethoxy, 3,4,2',6'-tetramethoxy and 3,4,2',4',6'-pentamethoxy-trans-stilbenes (MS) on human glioblastoma T98G cells. MATERIALS AND METHODS: The Parallel Artificial Membrane Permeation Assay (PAMPA) was used for the prediction of blood-brain barrier penetration ability of the tested stilbenes (PAMPA-BBB). MTT test was applied to analyze the cytotoxicity of the compounds, whereas their ability to inhibit Wnt/ß-catenin target genes expression was verified using qPCR. The potential DNA demethylating properties of the analyzed compounds were tested by Methylation-Sensitive High Resolution Melting (MS-HRM). Cell cycle distribution was tested using Fluorescence-Activated Cell Sorting (FACS), whereas apoptosis was analyzed using FITC Annexin V/propidium iodide double staining assay and Western blot. RESULTS: High blood-brain barrier permeability coefficient was obtained for both resveratrol as well as methoxy-stilbenes. Their ability to downregulate the expression of Wnt/ß-catenin pathway-related genes was confirmed. The 4'-methoxy substituted derivatives showed higher activity, whereas 3,4,4'-tri-MS was the most potent Wnt/ß-catenin pathway inhibitor. None of the compounds affected DNA methylation level of MGMT, SFRP1, or RUNX3, despite inducing moderate changes in the level of expression of epigenetic modifiers DNMT3B and TET1-3. Importantly, treatment with 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS led to cycle arrest in the S phase and induced apoptosis. CONCLUSIONS: Both, resveratrol, as well as its synthetic methoxy-derivatives, should be further studied as promising adjuvants in glioblastoma treatment.

11.
Mol Cell Biochem ; 476(2): 525-533, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33064289

RESUMO

Our previous study showed remarkable differences in the effect of R-sulforaphane (R-SFN) on the expression of CYPs 19, 1A1, 1A2, and 1B1 in ER(+) MCF7, ER( -) MDA-MB-231, and non-tumorigenic immortalized MCF10A (8). This study aimed to evaluate the effect of R-SFN on phase II enzymes induction and expression of AhR, Nrf2, and ERα in the same breast cell lines. The results showed increased expression of GSTP as a result of treatment with R-SFN in breast cancer cells. An increased NQO1 transcript and protein levels were found in all breast cells, with the most significant increase in MCF7 cells. Similarly, the enhancement of Nrf2 expression was noticed in all tested cells. AhR gene transcript and protein were decreased in MCF7 cells. In MDA-MB-231, increased AhR mRNA was not confirmed at the protein level. No differences were found in the expression of ERα. Overall, the results of the present study extended our earlier suggestions on the possible interference of R-SFN with estrogens homeostasis in breast cancer cells differing in ERα status, as well as in non-tumorigenic immortalized breast epithelial cells. While some of R-SFN effects might be beneficial and useful in breast cancer prevention, the others, particularly GSTP induction, may lead to adverse effects.

12.
Mol Cell Biochem ; 474(1-2): 113-123, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32737773

RESUMO

The present study aimed to evaluate the cytotoxicity and its mechanism of five synthetic methoxy stilbenes, namely 3,4,4'-trimethoxy, 3,4,2'-trimethoxy, 3,4,2',4'-tetramethoxy, 3,4,2',6'-tetramethoxy, and 3,4,2',4',6'-pentamethoxy-trans-stilbenes (MS), in comparison with resveratrol (RSV). Human promyelocytic (HL-60) and monocytic leukemia (THP-1) cells were treated with the tested compounds for 24 h, and cytotoxicity, cell cycle distribution, and apoptosis were evaluated. Significant differences were found in the susceptibility of these cell lines to all stilbenes, including RSV. The THP-1 cells were more resistant to cytotoxic activity of these compounds than HL-60 cells. Among the tested stilbenes, 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS exhibited higher cytotoxicity toward both cell lines than RSV and the other methoxy stilbenes. This activity might be related to cell cycle arrest at the G2/M phase and induction of apoptosis. In this regard, 3,4,4'-tri-MS and 3,4,2',4'-tetra-MS at highest concentrations increased the p53 protein level particularly in HL-60 cells. Moreover, treatment with these derivatives increased the ratio of the proapoptotic Bax protein to the antiapoptotic Bcl-xl protein, suggesting the induction of apoptosis through the intrinsic mitochondrial pathway in both cell lines. Further studies are required to fully elucidate the mechanism of these activities.


Assuntos
Apoptose , Pontos de Checagem do Ciclo Celular , Leucemia Mieloide/tratamento farmacológico , Resveratrol/análogos & derivados , Resveratrol/farmacologia , Estilbenos/química , Antioxidantes/farmacologia , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Células HL-60 , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
13.
Eur J Pharmacol ; 883: 173307, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668287

RESUMO

Our previous study demonstrated that new oleanolic acid oxime (OAO) derivatives and their conjugates with aspirin (ASP) inhibit NF-κB activation. Evidence exists that the downregulation of NF-κB negatively interferes with the Nrf2 signaling pathway. This study aimed to evaluate the effect of these compounds on Nrf2 activation and its cellular consequences in human hepatoma HepG2 cells and immortalized normal hepatocytes THLE-2. The results showed the enhanced activation and expression of Nrf2 as a result of treatment with OAO derivatives themselves and to less extent by their ASP conjugates, mainly in HepG2 cells. The association between cytotoxicity evaluated in our previous study and Nrf2 activation was observed. In this regard, compounds (18) with morpholide substituent at the C-17 position of OAO molecule and (12) with methyl ester substituent at the same position of OAO molecule to the most extent activated Nrf2 and subsequently cell cycle arrest at G2/M, leading to increased apoptosis and the number of resting HepG2 cells. The derivative of OAO (18) substituted with ASP (19) also affected Nrf2 activation and expression, but this effect was less pronounced in comparison with non-conjugated OAO. However, conjugation enhanced Nrf2 activation in normal THLE-2 cells. These results confirmed our earlier suggestion that OAO derivatives conjugated with ASP have the potential for application in the liver cancer chemoprevention. OAO themselves, particularly OAO substituted with morpholide, may be considered therapeutic agents, which may support conventional treatment strategy. Further studies are required to confirm this suggestion.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
14.
Acta Biochim Pol ; 67(1): 41-47, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129972

RESUMO

The chemical composition of Succisa pratensis is not well known. The existing data indicate a substantial content of flavonoids, which include luteolin and apigenin 7-glucosides. The aim of this study was to elaborate the isolation protocol of these flavonoids from flowers and leaves of S. pratensis, to carry out their characterization, as well as evaluate the effect of S. pratensis extracts on activation of transcription factor NF-κB and α-amylase activity. The extraction protocol applied in this study allowed isolation and characterization of flavonoid fraction of S. pratensis. Their identity was confirmed by NMR spectra analysis, UV spectroscopy and electrospray ionization-tandem MS evaluation. Treatment of pancreatic α-amylase with S. pratensis extract inhibited this enzyme's activity to an extent comparable to that of isolated luteolin and apigenin 7-glucosides. Incubation of HepG2 cells for 24 h with S. pratensis extracts or isolated flavonoids resulted in moderate reduction in NF-κB transcription factor activation evaluated in terms of translocation of its active subunits from cytosol into nucleus and subsequently diminished expression of the COX-2 gene. Expression of NF-κB was also reduced. The most significantly diminished NF-κB activation and expression, as well as COX-2 expression, was found to result from treatment with isolated flavonoids and ethyl acetate extract of S. pratensis leaves. These results indicate that S. pratensis flavonoids may modulate the metabolic and signaling pathways whose deregulation is related to pathogenesis of liver cancer. Further studies are required to confirm these observations and assess the chemopreventive and/or therapeutic potential of the S. pratensis herb.


Assuntos
Apigenina/farmacologia , Glucosídeos/farmacologia , Neoplasias Hepáticas/metabolismo , Luteolina/farmacologia , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , alfa-Amilases/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dipsacaceae/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Extratos Vegetais/uso terapêutico , alfa-Amilases/antagonistas & inibidores
15.
Int J Mol Sci ; 21(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046103

RESUMO

Targeting tumor cell motility and proliferation is an extremely important challenge in the prevention of metastasis and improving the effectiveness of cancer treatment. We recently published data revealing that DMU-214, the metabolite of firmly cytotoxic resveratrol analogue DMU-212, exerted significantly higher biological activity than the parent compound in ovarian cancer cells. The aim of the present study was to assess the molecular mechanism of the potential anti-migration and anti-proliferative effect of DMU-214 in ovarian cancer cell line SKOV-3. We showed that DMU-214 reduced the migratory capacity of SKOV-3 cells. The microarray analysis indicated ontology groups of genes involved in processes of negative regulation of cell motility and proliferation. Furthermore, we found DMU-214 triggered changes in expression of several migration- and proliferation-related genes (SMAD7, THBS1, IGFBP3, KLF4, Il6, ILA, SOX4, IL15, SRF, RGCC, GPR56) and proteins (GPR56, RGCC, SRF, SMAD7, THBS1), which have been shown to interact to each other to reduce cell proliferation and motility. Our study showed for the first time that DMU-214 displayed anti-migratory and anti-proliferative activity in SKOV-3 ovarian cancer cells. On the basis of whole transcriptome analysis of these cells, we provide new insight into the role of DMU-214 in inhibition of processes related to metastasis.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Ovarianas/metabolismo , Resveratrol/análogos & derivados , Estilbenos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Estilbenos/metabolismo , Transcriptoma
16.
Toxicol In Vitro ; 65: 104799, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32070777

RESUMO

Phytochemicals such as phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol (XAN), and resveratrol (RES) have been shown to target signaling pathways that are involved in the proliferation and survival of different pancreatic cancer (PC) cell lines. While the activity of these compounds alone was extensively studied, their combinations were never assessed. Thus, the aim of this study was to evaluate and compare the effect of PEITC, I3C, XAN, and RES and their combinations on the expression and activation of NF-κB and Nrf2 in human PC cell line PANC-1. The combination of XAN and PEITC was more efficient than the single compounds in reducing the binding of NF-κB p65 subunits to DNA by 47-60% and expression of p65 gene by 28-48%. The combination of XAN and PEITC also enhanced the activation and expression of Nrf2 and subsequently the expression of GSTP, NQO1, and SOD genes which are controlled by this transcription factor. Modulation of the activity of NF-κB and Nrf2 by the combination of XAN and PEITC was found to lead to reduced proliferation of PANC-1 cells. These results suggest that the combination of XAN and PEITC might be considered as a novel strategy for the prophylaxis and/or treatment of PC.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Flavonoides/farmacologia , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , Neoplasias Pancreáticas/metabolismo , Propiofenonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , NF-kappa B/metabolismo , Resveratrol/farmacologia
17.
Bioorg Chem ; 93: 103326, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586705

RESUMO

The aim of this study was to evaluate the effect of new oleanolic acid oxime (OAO) derivatives and their conjugates with aspirin (ASP) on the expression and activation of NF-κB in human hepatoma HepG2 cells. OAO derivatives showed a stronger cytotoxic effect against HepG2 cells compared with their conjugates with aspirin. Moreover, conjugation of OAO with ASP led to enhanced downregulation of NF-κB expression and activation. Among the hybrids with ASP, compounds: 19, 3-(2-acetoxy)benzoyloxyiminoolean-12-en-28-oic acid morpholide and 13, 3-(2-acetoxy)benzoyloxyiminoolean-12-en-28-oic acid methyl ester, differing, respectively, in morpholide and methyl ester groups at the C-17 position of oleanolic acid (OA) molecule were the most efficient. COX-2 transcript and protein levels were also diminished after treatment with these compounds. The results of this study indicate that the new derivatives of OAO and particularly their conjugates with ASP, downregulate the expression of COX-2 in HepG2 cells by modulating the NF-κB signaling pathway and suggest their potential application in the prevention of liver inflammation and cancer.


Assuntos
Aspirina/química , NF-kappa B/metabolismo , Ácido Oleanólico/farmacologia , Oximas/química , Transcrição Genética/efeitos dos fármacos , Células Hep G2 , Humanos , Ácido Oleanólico/química , Transdução de Sinais/efeitos dos fármacos
18.
Chem Biol Interact ; 311: 108786, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401087

RESUMO

Naturally occurring oleanolic acid (OA) possesses a hepatoprotective activity and ability to inhibit proliferation of human hepatocellular carcinoma cells. Both properties might be related to its anti-inflammatory activity. Its low bioavailability justifies the search for more hydrophilic OA derivatives. The aim of this study was the design and synthesis of four novel OA oxime derivatives conjugated with succinic acid at the C-3 position of oleanane skeleton structure and evaluation of their effect on NF-κB and STATs expression and activation in HepG2 cells. The expression of NF-κB and cyclooxygenase-2 (COX-2), STAT5A/B and STAT3 with its target genes: BAX, BCL-XL and MYC was evaluated after 24 h treatment with tested compounds. The comparison of the levels of cytosolic and nuclear NF-κB subunits p50, p65 and STATs proteins was used as the measure of their activation. The results pointed out the 3-succinyloxyiminoolean-12-en-28-oic acid morpholide (SMAM) as the most potent modulator of NF-κB and STAT3. SMAM significantly reduced the expression and activation of NF-κB as well as its nuclear protein level of p65 subunit. This compound also reduced the expression and activation of STAT3 and STAT5A/B. Combined effect of SMAM on these transcription factors resulted in reduced expression of COX-2, MYC and anti-apoptotic BCL-XL genes. Simultaneously, the increased expression of pro-apoptotic BAX gene was observed. In the cells treated with 3-succinyloxyiminoolean-12-en-28-oic acid (SMAA) the increased expression of BAX was also found. The effects of 3-succinyloxyiminoolean-12-en-28-oic acid benzyl ester (SMAEB) and 3-succinyloxyiminoolean-12-en-28-oic acid methyl ester (SMAEM) were moderate and ambiguous in relation to the tested factors. Moreover, the coordinated action of SMAM on NF-κB and STAT3 confirms their close association in HepG2 cells. We conclude that SMAM efficiently downregulates the key elements of signaling pathways involved in inflammatory driven HCC. Thus, may be considered as a potential chemopreventive or therapeutic agent in this type of cancer.


Assuntos
NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Oximas/farmacologia , Fatores de Transcrição STAT/metabolismo , Ácido Succínico/química , Carcinoma Hepatocelular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , NF-kappa B/genética , Oximas/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/genética , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
19.
Cell Oncol (Dordr) ; 42(4): 505-520, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089983

RESUMO

PURPOSE: Activation of the Wnt pathway contributes to the development of head and neck squamous cell carcinomas (HNSCC) and its inhibition has recently emerged as a promising therapeutic strategy. Here, we aimed at identifying suitable molecular targets for down-regulation of canonical Wnt signaling in HNSCC cells. METHODS: Candidate target genes (PORCN, WNT3A, FZD2, FZD5, LRP5, DVL1, CIP2A, SET, KDM1A, KDM4C, KDM6A, CBP, CARM1, KMT2A, TCF7, LEF1, PYGO1, XIAP) were silenced using siRNA and selected targets were subsequently blocked using small molecule inhibitors. The effect of this treatment on the expression of ß-catenin-dependent genes was assessed by qRT-PCR. The effect of the inhibitors on cell viability was evaluated using a resazurin assay in HNSCC-derived cell lines. A luciferase reporter assay was used for confirmation of the inhibition of Wnt-dependent gene expression. Cell migration was evaluated using a scratch wound healing assay. Cytometric analysis of propidium iodide stained cells was used for cell cycle distribution evaluation, whereas cytometric analysis of caspase 3/7 activity was used for apoptosis induction evaluation. RESULTS: We found that inhibition of Porcupine and CBP/ß-catenin interaction by IWP-2 and PRI-724, respectively, most strongly affected ß-catenin-dependent gene expression in HNSCC cells. These inhibitors also induced apoptosis and affected HNSCC cell migration. CONCLUSIONS: Targeting Porcupine or the CBP/ß-catenin interaction seems to be an effective strategy for the inhibition of canonical Wnt signaling in HNSCC cells. Further studies are required to confirm the possible therapeutic effect of IWP-2 and PRI-724 in HNSCC.


Assuntos
Aciltransferases/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/patologia , Proteínas de Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Sialoglicoproteínas/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia , Survivina/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
20.
Int J Mol Sci ; 21(1)2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31892167

RESUMO

Pomegranate juice is a rich source of ellagitannins (ETs) believed to contribute to a wide range of pomegranate's health benefits. While a lot of experimental studies have been devoted to Alzheimer disease and hypoxic-ischemic brain injury, our knowledge of pomegranate's effects against Parkinson's disease (PD) is very limited. It is suggested that its neuroprotective effects are mediated by ETs-derived metabolites-urolithins. In this study, we examined the capability of pomegranate juice for protection against PD in a rat model of parkinsonism induced by rotenone. To evaluate its efficiency, assessment of postural instability, visualization of neurodegeneration, determination of oxidative damage to lipids and α-synuclein level, as well as markers of antioxidant defense status, inflammation, and apoptosis, were performed in the midbrain. We also check the presence of plausible active pomegranate ETs-derived metabolite, urolithin A, in the plasma and brain. Our results indicated that pomegranate juice treatment provided neuroprotection as evidenced by the postural stability improvement, enhancement of neuronal survival, its protection against oxidative damage and α-synuclein aggregation, the increase in mitochondrial aldehyde dehydrogenase activity, and maintenance of antiapoptotic Bcl-xL protein at the control level. In addition, we have provided evidence for the distribution of urolithin A to the brain.


Assuntos
Encéfalo/efeitos dos fármacos , Cumarínicos/metabolismo , Taninos Hidrolisáveis/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Romã (Fruta)/química , Animais , Antioxidantes/metabolismo , Frutas/química , Sucos de Frutas e Vegetais , Masculino , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...