Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.069
Filtrar
1.
PLoS One ; 15(9): e0238509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870935

RESUMO

Dendrobium bibenzyls and phenanthrenes such as chrysotoxine, cypripedin, gigantol and moscatilin have been reported to show promising inhibitory effects on lung cancer growth and metastasis in ex vivo human cell line models, suggesting their potential for clinical application in patients with lung cancer. However, it remains to be determined whether these therapeutic effects can be also seen in primary human cells and/or in vivo. In this study, we comparatively investigated the immune modulatory effects of bibenzyls and phenanthrenes, including a novel Dendrobium bibenzyl derivative, in primary human monocytes. All compounds were isolated and purified from a Thai orchid Dendrobium lindleyi Steud, a new source of therapeutic compounds with promising potential of tissue culture production. We detected increased frequencies of TNF- and IL-6-expressing monocytes after treatment with gigantol and cypripedin, whereas chrysotoxine and moscatilin did not alter the expression of these cytokines in monocytes. Interestingly, the new 4,5-dihydroxy-3,3',4'-trimethoxybibenzyl derivative showed dose-dependent immune modulatory effects in lipopolysaccharide (LPS)-treated CD14lo and CD14hi monocytes. Together, our findings show immune modulatory effects of the new bibenzyl derivative from Dendrobium lindleyi on different monocyte sub-populations. However, therapeutic consequences of these different monocyte populations on human diseases including cancer remain to be investigated.


Assuntos
Bibenzilas/farmacologia , Dendrobium , Fatores Imunológicos/farmacologia , Monócitos/efeitos dos fármacos , Fenantrenos/farmacologia , Extratos Vegetais/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Bibenzilas/química , Células Cultivadas , Dendrobium/química , Guaiacol/análogos & derivados , Guaiacol/química , Guaiacol/farmacologia , Humanos , Fatores Imunológicos/química , Monócitos/imunologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Fenantrenos/química , Extratos Vegetais/química
2.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878797

RESUMO

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Survivina/genética , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 40(9): 5115-5124, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878800

RESUMO

BACKGROUND/AIM: Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells. MATERIALS AND METHODS: Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The anti-metastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined. RESULTS: PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species. CONCLUSION: Shikonin may be a novel therapeutic agent for patients with CCA.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Colangiocarcinoma/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Hormônios Tireóideos
4.
Cancer Invest ; 38(8-9): 476-485, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32845783

RESUMO

Cancer has emerged as a major public health issue in developed as well as in developing countries. Plant-derived molecules are widely being used in the treatment of cancer due to their minimum side effects. Lawsonia inermis (Henna) is one of the medicinal plants containing many therapeutic properties. In the present study, bioactive components of L. inermis extract were analyzed by LCMS/MS method and validated. Lawsone (3.5%) is primarily responsible for cytotoxic and anti-cancerous activities. These properties were studied on human lung carcinoma (A549), colorectal cancer (DLD1) and Hepatocellular carcinoma (HepG2) cancer cell lines. The activities were assessed by MTT assay, evaluation of apoptosis by measuring the production of Reactive Oxygen Species (ROS) and mitochondrial membrane potential of the cancer cell lines. Moreover, apoptosis in the respective cancer cell lines was also determined by chromatin condensation and DNA fragmentation using Hoechst 33528 and propidium iodide (PI) staining. The preliminary in vitro result of MTT showed that the henna extract induces cytotoxic properties against A549, DLD1, HepG2 with IC50values 490, 480 and 610 µg/ml respectively (more than 40% growth inhibition). In addition, the extract induced a concentration-dependent rise in ROS production which was 84, 102, and 110% in HepG2, DLD1 AND A549 respectively at 300 µg/ml, whereas at 400 µg/ml concentration it was 86, 102, and 106% in respective cell lines while decreasing mitochondrial membrane potential was more than 20% in the investigated cell lines. The extract also provoked changes associated with apoptosis and the data indicate that the ROS production leads to a diminution in mitochondrial membrane potential and this correlated with the extract cytotoxicity.


Assuntos
Lawsonia (Planta)/química , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Cromatografia Líquida , Neoplasias Colorretais/tratamento farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/análise , Naftoquinonas/farmacologia , Extratos Vegetais/análise , Espectrometria de Massas em Tandem
5.
Environ Toxicol ; 35(12): 1374-1385, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32691977

RESUMO

Cardiovascular disease created enormous health and economic burdens worldwide, which is responsible for the highest mobility and mortality that results in nearly 6.2% of in-hospital deaths every year. Plumbagin is a major bioactive compound that occurs in the Plumbago indica and P. zeylanica with numerous therapeutic benefits. The current research exploration was planned to investigate the therapeutic role of plumbagin against doxorubicin stimulated cardiotoxicity in rats. The cardiotoxicity was stimulated to the rats by administering the 2.5 mg/kg of doxorubicin for 14 days with concurrent supplementation with plumbagin. The hemodynamic parameters were studied by using the tail-cuff plethysmography. The lipid peroxidation and antioxidant status was examined by the standard procedures. The myocardial function and damage markers were assessed with the help of commercial kits. The expression status of inflammatory markers and PI3K/Akt signaling markers were investigated by reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis, respectively. The plumbagin supplementation appreciably regained the body weight and heart weight of the investigational animals. Hemodynamic parameters and antioxidants statuses were escalated by the plumbagin treatment. The severe elevation in the cardiac damage markers and inflammatory markers were noticeably ameliorated by the plumbagin treatment. The plumbagin treatment also assuaged the overexpression of inflammatory and apoptotic proteins in the heart tissues of doxorubicin-challenged rats. The histopathological analysis revealed that the plumbagin appreciably protected the heart tissues from the doxorubicin-induced damages. The findings of this exploration evidenced that plumbagin treatment attenuated the doxorubicin-stimulated cardiotoxicity in rats.


Assuntos
Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Miocárdio , Naftoquinonas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/sangue , Cardiotoxicidade , Citocinas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
6.
Chem Biol Interact ; 327: 109142, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32610056

RESUMO

Juglone and thymoquinone are cytotoxic to pancreatic cancer cells. The aim of this study was to investigate, using an analysis of isobolograms, the type and degree of interactions between juglone and thymoquinone on MIA PaCa-2 pancreatic cancer cells. Cell viability was evaluated using the MTT assay. Cell death was determined by flow cytometry. The IC50 value for juglone and TQ in combination was found to be 24.75 µM, which was higher than juglone or TQ alone. Juglone alone killed Mia Paca-2 cells by ferroptosis. At concentrations where 10, 20 or 50% of cells were affected, there existed a moderate antagonistic relationship between juglone and TQ as indicated by the combination index (CI) value determined by the Compusyn software. At concentrations that affected 75% and 90% of cells, there were nearly an additive effect with CI value of 1.09249 and 0.92391, respectively. Moderate synergism was only seen at concentration where 95% of cells were affected, and the corresponding concentration of juglone and TQ at that combination was 40.90 µM and 511.19 µM, respectively.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Naftoquinonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos
7.
Medicine (Baltimore) ; 99(22): e20450, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481450

RESUMO

BACKGROUND: This study will investigate the effect of shikonin on the proliferation and apoptosis of human ovarian cancer cell SKOV3 (HOCC-SKOV3). METHODS: We will retrieve potential studies from inception to the March 1, 2020 in Cochrane Library, MEDLINE, EMBASE, Scopus, Cumulative Index to Nursing and Allied Health Literature, WANGFANG, and China National Knowledge In-frastructure. There are not restrictions related to the language and publication status. This study will include case-controlled studies (CCSs) or randomized controlled studies (RCSs) that examine the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3. Two researchers will independently identify literatures, extract data, and appraise study quality. Any disagreements will be resolved by discussion with another researcher. RevMan 5.3 software will be placed to perform statistical analysis. RESULTS: This study will summarize the present evidence to test the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3. CONCLUSION: It will provide evidence to investigate the effect of shikonin on the proliferation and apoptosis of HOCC-SKOV3, and will supply reference for further study.Systematic review registration: INPLASY202040146.


Assuntos
Antineoplásicos/farmacologia , Cistadenocarcinoma Seroso/tratamento farmacológico , Metanálise como Assunto , Naftoquinonas/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Revisões Sistemáticas como Assunto , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/fisiopatologia , Feminino , Humanos , Neoplasias Ovarianas/fisiopatologia
8.
Arch Oral Biol ; 116: 104774, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32470830

RESUMO

OBJECTIVES: The aim of the present study was to identify the anticancer effects and the mechanisms of action of shikonin and its analogue isobutyrylshikonin in oral squamous carcinoma cells. DESIGNS: The cytotoxic effects of isobutyrylshikonin and shikonin in Ca9-22 and SCC-25 cells were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry analysis of Annexin V/Propidium Iodide (PI) staining, western blot analysis and immunohistochemistry. RESULTS: Treatment with both isobutyrylshikonin and shikonin induced dose- and time-dependent apoptotic cell death in Ca9-22 cells, although the IC50 of isobutyrylshikonin was less than that of shikonin. The induction of apoptosis by both isobutyrylshikonin and shikonin was accompanied by activation of caspase-8, -9, -3, and PARP, loss of mitochondrial trans-membrane potential, and release of cytochrome c from the mitochondria. ROS mediated the apoptosis induced by isobutyrylshikonin and shikonin, indicating that ROS may play a critical role in the distinctive cytotoxic effects of isobutyrylshikonin and shikonin in Ca9-22. Isobutyrylshikonin showed a similar cytotoxic effect in SCC-25 cells at concentrations showing the effects in Ca9 cells, but not in human normal keratinocyte cells. Although there is no biological difference between isobutyrylshikonin and shikonin, isobutyrylshikonin exerts the same cytotoxic effect at a concentration 6 times lower than shikonin. CONCLUSIONS: The present study suggest that isobutyrylshikonin may be a more potent chemotherapeutic agent against oral cancer cells than shikonin. In addition, our data exhibit that both isobutyrylshikonin and shikonin induce caspase-dependent apoptosis via the mitochondrial pathway through accumulation of ROS in oral squamous carcinoma cells.


Assuntos
Neoplasias Bucais , Naftoquinonas , Apoptose , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial , Neoplasias Bucais/tratamento farmacológico , Naftoquinonas/farmacologia , Naftoquinonas/toxicidade , Espécies Reativas de Oxigênio , Células Tumorais Cultivadas
9.
Medicine (Baltimore) ; 99(17): e19848, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332640

RESUMO

Xiakemycin A (XKA), a new antibiotic in the pyranonaphthoquinone family, shows antitumor activity. However, the type of cell death induced by XKA remains elusive. In this study, we aim to investigate the type of death induced by XKA in hepatic cancer.The apoptotic features, such as chromatic agglutination, reactive oxygen species generation and membrane potential of mitochondria, in HepG2 cells treated by XKA were measured by Hoechst 33342 staining and flow cytometry. Apoptosis of HepG2 cells treated with XKA was determined by Annexin V-FITC/propidium iodide double staining and Western blot analysis, respectively.XKA had a significant dose-dependent elevation of chromatic agglutination, reactive oxygen species generation, Annexin V and propidium iodide staining, decrease of membrane potential. Meanwhile, in apoptotic HepG2 cells induced by XKA, robust increment was noticed in p53 expression, cleavage of PARP, caspase-3, and caspase-9.XKA showed potent inhibitory effects on the proliferation of HepG2 cells. Such phenomenon may be related to activation of the apoptotic pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Naftoquinonas/farmacologia , Anexina A5/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Caspase 3/metabolismo , Caspase 9/metabolismo , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias Hepáticas/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Propídio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Biochim Biophys Acta Bioenerg ; 1861(8): 148210, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305410

RESUMO

An increase in the production of reactive oxygen species (ROS) in mitochondria due to targeted delivery of redox active compounds may be useful in studies of modulation of cell functions by mitochondrial ROS. Recently, the mitochondria-targeted derivative of menadione (MitoK3) was synthesized. However, MitoK3 did not induce mitochondrial ROS production and lipid peroxidation while exerting significant cytotoxic action. Here we synthesized 1,4-naphthoquinone conjugated with alkyltriphenylphosphonium (SkQN) as a prototype of mitochondria-targeted prooxidant, and its redox properties, interactions with isolated mitochondria, yeast cells and various human cell lines were investigated. According to electrochemical measurements, SkQN was more active redox agent and, due to the absence of methyl group in the naphthoquinone ring, more reactive as electrophile than MitoK3. SkQN (but not MitoK3) stimulated hydrogen peroxide production in isolated mitochondria. At low concentrations, SkQN stimulated state 4 respiration in mitochondria, decreased membrane potential, and blocked ATP synthesis, being more efficient uncoupler of oxidative phosphorylation than MitoK3. In yeast cells, SkQN decreased cell viability and induced oxidative stress and mitochondrial fragmentation. SkQN killed various tumor cells much more efficiently than MitoK3. Since many tumors are characterized by increased oxidative stress, the use of new mitochondria-targeted prooxidants may be a promising strategy for anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Naftoquinonas/química , Fosforilação Oxidativa/efeitos dos fármacos , Oxigênio/metabolismo , Compostos de Fósforo/química , Espécies Reativas de Oxigênio/química
11.
J Enzyme Inhib Med Chem ; 35(1): 773-785, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32200656

RESUMO

Basis on molecular docking and pharmacophore analysis of naphthoquinone moiety, a total of 23 compounds were designed and synthesised. With the help of reverse targets searching, anti-cancer activity was preliminarily evaluated, most of them are effective against some tumour cells, especially compound 12: 1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl-4-oxo-4-((4-phenoxyphenyl)amino) butanoate whose IC50 against SGC-7901 was 4.1 ± 2.6 µM. Meanwhile the anticancer mechanism of compound 12 had been investigated by AnnexinV/PI staining, immunofluorescence, Western blot assay and molecular docking. The results indicated that this compound might induce cell apoptosis and cell autophagy through regulating the PI3K signal pathway.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Naftoquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
mBio ; 11(1)2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019788

RESUMO

Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monasones) reside within the gene cluster for Monascus azaphilone pigments (MonAzPs). We elucidate the biosynthetic pathway of monasones by a combination of comparative genome analysis, gene knockouts, heterologous coexpression, and in vivo and in vitro enzymatic reactions to show that this pathway branches from the first polyketide intermediate of MonAzPs. Furthermore, we propose that the monasone subset of biosynthetic genes also encodes a two-tiered resistance strategy in which an inducible monasone-specific exporter expels monasones from the mycelia, while residual intracellular monasones may be rendered nontoxic through a multistep reduction cascade.IMPORTANCE The genes for Monascus naphthoquinone (monasone) biosynthesis are embedded in and form a composite supercluster with the Monascus azaphilone pigment biosynthetic gene cluster. Early biosynthetic intermediates are shared by the two pathways. Some enzymes encoded by the supercluster play double duty in contributing to both pathways, while others are specific for one or the other pathway. The monasone subcluster is independently regulated and inducible by elicitation with competing microorganisms. This study illustrates genomic and biosynthetic parsimony in fungi and proposes a potential path for the evolution of the mosaic-like azaphilone-naphthoquinone supercluster. The monasone subcluster also encodes a two-tiered self-resistance mechanism that models resistance determinants that may transfer to target microorganisms or emerge in cancer cells in case of naphthoquinone-type cytotoxic agents.


Assuntos
Monascus/efeitos dos fármacos , Monascus/genética , Família Multigênica , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Vias Biossintéticas , Farmacorresistência Fúngica/genética , Monascus/metabolismo
13.
J Antibiot (Tokyo) ; 73(5): 324-328, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32051568

RESUMO

Lavanducyanin is a bioactive phenazine-containing secondary metabolite, and naphthomevalin is an antibacterial polyketide secondary metabolite. Herein, new analogues of lavanducyanin (2) and of naphthomevalin (4), together with lavanducyanin (1) and naphthomevalin (3), were identified from Streptomyces sp. CPCC 203577, an actinomycete soil isolate. The structures of 2 and 4 were elucidated as 1-hydroxy-7-oxolavanducyanin and Δ7″,8″-6″-hydroxynaphthomevalin, respectively, by 1D and 2D NMR. Antibacterial assays revealed that 2 had significant but reduced anti-Gram-positive bacterial activity compared with 1, and 4 was devoid of anti-Gram-positive bacterial activity. This indicated that the phenazinone nucleus in lavanducyanin and the monoterpene side chain in naphthomevalin might be important for their anti-Gram-positive bacterial activity. Compounds 1-4 were all inactive against Gram-negative bacteria.


Assuntos
Antibacterianos/farmacologia , Fenazinas/farmacologia , Streptomyces/metabolismo , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bactérias Gram-Negativas/química , Bactérias Gram-Positivas/química , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Fenazinas/química , Fenazinas/isolamento & purificação , Metabolismo Secundário , Microbiologia do Solo , Streptomyces/isolamento & purificação , Relação Estrutura-Atividade
14.
Drug Des Devel Ther ; 14: 577-589, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103900

RESUMO

Background: Shikonin, the main ingredient of Lithospermum erythrorhizon, has been reported to have antitumor effects via multiple targets and signaling pathways. However, the detailed mechanism underlying the effects in cervical cancer still remained unknown. Methods: MTT, wound-healing, transwell assays and flow cytometry experiments were used to measure cell growth, migration, invasion, and cell cycle analysis. Western blot was used to examine protein levels of Snail, Vimentin and E-cadherin. The expression level of miR-183-5p was measured via qRT-PCR. The E-cadherin promoter activity was detected via Secrete-PairTM Dual Luminescence Assay Kit. The transient transfection experiments were used for silencing of E-cadherin and overexpression of Snail genes. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings. Results: We showed that shikonin inhibited cell viability, migration and invasion, and induced cell cycle arrest in a dose-dependent manner in cervical cancer Hela and C33a cells. Mechanistically, we found that shikonin increased miR-183-5p expression and inhibited expression of transcription factor Snail protein. The mimics of miR-183-5p reduced, while the inhibitors of miR-183-5p reversed shikonin-inhibited Snail protein expression. In addition, shikonin decreased Vimentin, increased E-cadherin protein expressions and E-cadherin promoter activity, the latter was reversed in cells transfected with exogenous Snail overexpression vectors. Moreover, silencing of E-cadherin significantly abolished shikonin-inhibited cervical cancer cell growth. Similar findings were also observed in vivo using one xenograft mouse model. Conclusion: Our results show that shikonin inhibits EMT through inhibition of Snail and stimulation of miR-183-5p expressions, which resulted in induction of E-cadherin expression. Thus, blockade of EMT could be a novel mechanism underlying the anti-cervical cancer effects of shikonin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , MicroRNAs/genética , Naftoquinonas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antígenos CD/genética , Antineoplásicos Fitogênicos/administração & dosagem , Caderinas/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Lithospermum/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftoquinonas/administração & dosagem , Fatores de Transcrição da Família Snail/genética , Neoplasias do Colo do Útero/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Molecules ; 25(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013142

RESUMO

Twelve 1, 4-naphthoquinone derivatives, including two new (1 and 2) and 10 known (3-12), were obtained from endophytic fungus Talaromyces sp. SK-S009 isolated from the fruit of Kandelia obovata. All structures were identified through extensive analysis of the nuclear magnetic resonance (NMR), mass spectrometry (MS) and circular dichroism (CD), as well as by comparison with literature data. These compounds significantly inhibited the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in the murine macrophage cell line (RAW 264.7 cells). The half maximal inhibitory concentration (IC50) values, except for compound 2, were lower than that of indomethacin (26.3 µM). Compound 9 inhibited the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expressions in RAW 264.7 macrophages. Additionally, compound 9 reduced the mRNA levels of pro-inflammatory factors interleukin (IL)1ß, IL-6, and tumor necrosis factor (TNF)-α. The results of this study demonstrated that these 1, 4-naphthoquinone derivatives can inhibit LPS-induced inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Naftoquinonas/farmacologia , Talaromyces/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real
16.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085381

RESUMO

This review aims to explore the potential of resveratrol, a polyphenol stilbene, and beta-lapachone, a naphthoquinone, as well as their derivatives, in the development of new drug candidates for cancer. A brief history of these compounds is reviewed along with their potential effects and mechanisms of action and the most recent attempts to improve their bioavailability and potency against different types of cancer.


Assuntos
Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Antineoplásicos/química , Humanos , Concentração Inibidora 50 , Naftoquinonas/química , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo
17.
Food Chem ; 316: 126339, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32044704

RESUMO

This study investigated the bioactivities of polyhydroxyl-1,4-naphthoquinone (PHNQ) extracts from Evechinus chloroticus shell waste. PHNQs were extracted from E. chloroticus shells and spines using different solvents and the crude extracts were fractionated by HPLC. The antioxidant activity of the PHNQ extracts were evaluated by the DPPH, ABTS, ORAC and FRAP assays. Ethyl acetate was the best extraction solvent and spine extracts showed better antioxidant activity than shell extracts (p < 0.05). The HPLC fraction containing spinochrome E showed the highest antioxidant activity (p < 0.05). The Minimum Inhibitory Concentration of the PHNQ crude extracts and the HPLC fractions ranged from 250 to 2500 µg/mL depending on the PHNQ extract and microbial species tested. Treatment by PHNQ extracts resulted in alteration of the morphology of the microbial cell wall as observed by transmission electron microscopy. PHNQ extracts also exhibited anti-inflammatory activity in rats (ED50 = 8.26 ± 0.22 µg), comparable to that of Celecoxib (6.12 ± 0.18 µg).


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Naftoquinonas/farmacologia , Ouriços-do-Mar/química , Animais , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley
18.
Mol Carcinog ; 59(4): 399-411, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027051

RESUMO

Exploiting metabolic vulnerabilities of cancer cells with nontoxic, plant derived compounds constitutes a novel strategy for both chemoprevention and treatment. A high-throughput screening approach was used to evaluate a library of natural products to determine the most synergistic combination in precursor-B cell acute lymphoblast leukemia. Dimethylaminoparthenolide and shikonin effectively inhibited proliferation resulting in cell death in primary and immortalized leukemia cells, while having negligible effects on normal cells. Dimethylaminoparthenolide and shikonin have been shown separately to inhibit cell survival and proliferative signaling and activate tumor suppressors and proapoptotic pathways. Untargeted metabolomics and metabolic flux analysis with stable isotopically labeled glucose and glutamine exhibited a global shift in metabolism following treatment. Pathway analysis indicated significant differences in amino acid, antioxidant, tricarboxylic acid cycle, and nucleotide metabolism. Together, dimethylaminoparthenolide and shikonin reduced the shunting of glycolytic intermediates into the pentose phosphate pathway for biosynthetic purposes. Similarly, the incorporation of glutamine and glutamine-derived metabolites into purine and pyrimidine synthesis was inhibited by the combination of dimethylaminoparthenolide and shikonin, effectively impeding biosynthetic pathways critical for leukemia cell survival. This approach demonstrates that a synergistic pair of compounds with malignant cell specificity can effectively target metabolic pathways crucial to leukemia cell proliferation and induce apoptosis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Naftoquinonas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Glucose/metabolismo , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
19.
PLoS One ; 15(2): e0228657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017790

RESUMO

Plumbagin derived from the plant Plumbago indica, known as Chitrak in India, is an example of a medicinal compound used traditionally to cure a variety of ailments. Previous reports have indicated that it can inhibit the growth of Mycobacterium tuberculosis (Mtb), the causative agent of the deadly disease TB. In this investigation, we provide an insight into its mode of action. We show here that a significant mycobacterial target that is inhibited by plumbagin is the enzyme ThyX, a form of thymidylate synthase, that is responsible for the synthesis of dTMP from dUMP in various bacterial pathogens, including Mtb. Using a purified preparation of the recombinant version of Mtb ThyX, we demonstrate that plumbagin, a 2,4 napthoquinone, but not lawsone, a structurally related medicinal compound, inhibits its activity in vitro. We also show that the intracellular [dTTP]/[dATP] ratio in Mycobacterium smegmatis (Msm) cells decrease upon treatment with plumbagin, and this, in turn, leads to cell death. Such a conclusion is supported by the observation that over-expression of thyx in the plumbagin treated Msm cells leads to the restoration of viability. The results of our investigation indicate that plumbagin kills mycobacterial cells primarily by targeting ThyX, a vital enzyme required for their survival.


Assuntos
Mycobacterium tuberculosis/enzimologia , Naftoquinonas/farmacologia , Timidilato Sintase/antagonistas & inibidores , Antituberculosos , Produtos Biológicos , Sobrevivência Celular/efeitos dos fármacos , Nucleotídeos de Desoxiadenina/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Naftoquinonas/uso terapêutico , Nucleotídeos de Timina/metabolismo
20.
Phytomedicine ; 68: 153149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032836

RESUMO

BACKGROUND: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China. PURPOSE: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2. RESULTS: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein. CONCLUSION: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization.


Assuntos
Anafilaxia/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas do Tecido Nervoso/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Receptores de Neuropeptídeos/imunologia , Anafilaxia/induzido quimicamente , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Hipersensibilidade/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Naftoquinonas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Fosfolipase C gama/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Secretagogos/toxicidade , p-Metoxi-N-metilfenetilamina/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA