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1.
Mol Carcinog ; 58(9): 1680-1690, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31211467

RESUMO

Treatment with vemurafenib, a potent and selective inhibitor of mitogen-activated protein kinase signaling downstream of the BRAFV600E oncogene, elicits dramatic clinical responses in patients with metastatic melanoma. Unfortunately, the clinical utility of this drug is limited by a high incidence of drug resistance. Thus, there is an unmet need for alternative therapeutic strategies to treat vemurafenib-resistant metastatic melanomas. We have conducted high-throughput screening of two bioactive compound libraries (Siga and Spectrum libraries) against a metastatic melanoma cell line (A2058) and identified two structurally analogous compounds, deguelin and rotenone, from a cell viability assay. Vemurafenib-resistant melanoma cell lines, A2058R and A375R (containing the BRAFV600E mutation), also showed reduced proliferation when treated with these two compounds. Deguelin, a mitochondrial complex I inhibitor, was noted to significantly inhibit oxygen consumption in cellular metabolism assays. Mechanistically, deguelin treatment rapidly activates AMPK signaling, which results in inhibition of mTORC1 signaling and differential phosphorylation of mTORC1's downstream effectors, 4E-BP1 and p70S6 kinase. Deguelin also significantly inhibited ERK activation and Ki67 expression without altering Akt activation in the same timeframe in the vemurafenib-resistant melanoma cells. These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug-resistant melanomas harboring BRAF V600E mutations.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Rotenona/análogos & derivados , Vemurafenib/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Melanoma/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação/efeitos dos fármacos , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos
2.
Cancer ; 125(11): 1789-1798, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933320

RESUMO

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Desenvolvimento de Medicamentos , Neoplasias/tratamento farmacológico , Rotenona/análogos & derivados , Animais , Humanos , Rotenona/uso terapêutico
3.
Bioorg Med Chem ; 27(7): 1370-1381, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30827868

RESUMO

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 167: 485-498, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784881

RESUMO

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
6.
Neuropharmacology ; 149: 133-148, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772375

RESUMO

Leptin is produced in the adipocytes and plays a pivotal role in regulation of energy balance by controlling appetite and metabolism. Leptin receptors are widely distributed in the brain, especially in the hypothalamus, hippocampus, and neocortex. The insular cortex (IC) processes gustatory and visceral information, which functionally correlate to feeding behavior. However, it is still an open issue whether and how leptin modulates IC neural activities. Our paired whole-cell patch-clamp recordings using IC slice preparations demonstrated that unitary inhibitory postsynaptic currents (uIPSCs) but not uEPSCs were potentiated by leptin in the connections between pyramidal (PNs) and fast-spiking neurons (FSNs). The leptin-induced increase in uIPSC amplitude was accompanied by a decrease in paired-pulse ratio. Under application of inhibitors of JAK2-PI3K but not MAPK pathway, leptin did not change uIPSC amplitude. Variance-mean analysis revealed that leptin increased the release probability but not the quantal size and the number of release site. These electrophysiological findings suggest that the leptin-induced uIPSC increase is mediated by activation of JAK2-PI3K pathway in presynaptic FSNs. An in vivo optical imaging revealed that leptin application decreased excitatory propagation in IC induced by electrical stimulation of IC. These leptin-induced effects were not observed under the low energy states: low glucose concentration (2.5 mM) in vitro and one-day-fasting condition in vivo. However, leptin enhanced uIPSCs under application of low glucose with an AMPK inhibitor. These results suggest that leptin suppresses IC excitation by facilitating GABA release in FSN→PN connections, which may not occur under a hunger state.


Assuntos
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Leptina/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Cromonas/farmacologia , Excitabilidade Cortical/efeitos dos fármacos , Estimulação Elétrica , Flavonoides/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Glucose/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Morfolinas/farmacologia , Técnicas de Patch-Clamp , Cultura Primária de Células , Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Transgênicos , Rotenona/análogos & derivados , Rotenona/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Wortmanina/farmacologia
7.
Bioorg Med Chem Lett ; 29(1): 89-96, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446312

RESUMO

The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPß, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPα and PPARγ and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down-regulation of critical adipogenic transcription factors, including C/EBPß, C/EBPα, and PPARγ, through activation of the AMPK signaling pathway by rotenoisin A.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Rotenona/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Fármacos Antiobesidade/química , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Rotenona/análogos & derivados , Rotenona/química , Relação Estrutura-Atividade
8.
J Cell Physiol ; 234(3): 2719-2729, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30078209

RESUMO

Excessive bone resorption by osteoclasts (OCs) plays an important role in lytic bone diseases, such as osteoporosis. Although the pharmacological treatment of osteoporosis has been extensively developed, alternative treatments are still needed. Deguelin, a rotenoid isolated from several plant species, is a strong antitumor agent; however, its effect on OCs remains unclear. To the best of our knowledge, this is the first study to report that deguelin inhibits the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis, messenger RNA expression of osteoclastic-specific genes, and osteoclastic bone resorption, in primary bone marrow-derived macrophages. At the molecular level, deguelin markedly blocked RANKL-induced osteoclastogenesis by attenuating the phosphorylation of NF-κB p65 and inhibiting p65 nuclear translocation. In addition, deguelin suppressed the downstream expression of nuclear factor of activated T-cell cytoplasmic 1, which is a crucial transcription factor in OC differentiation. Consistent with the in vitro results, deguelin inhibited lipopolysaccharide-induced bone resorption by suppressing osteoclastogenesis. Taken together, our findings reveal that deguelin has antiosteoclastic effects in vitro and in vivo and possesses potential as a new therapeutic option for osteolytic bone diseases.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Inflamação/patologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Rotenona/análogos & derivados , Animais , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos
9.
Viruses ; 10(11)2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405048

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus for which there is no vaccine or cure. This viral infection, once acquired, is life-long, residing latently in hematopoietic cells. However, latently infected individuals with weakened immune systems often undergo HCMV reactivation, which can cause serious complications in immunosuppressed and immunocompromised patients. Current anti-viral therapies target late stages of viral replication, and are often met with therapeutic resistance, necessitating the development of novel therapeutics. In this current study, we identified a naturally-occurring flavonoid compound, deguelin, which inhibits HCMV lytic replication. Our findings reveal that nanomolar concentrations of deguelin significantly suppress the production of the infectious virus. Further, we show that deguelin inhibits the lytic cycle during the phase of the replication cycle consistent with early (E) gene and protein expression. Importantly, our data reveal that deguelin inhibits replication of a ganciclovir-resistant strain of HCMV. Together, our findings identify a novel, naturally occurring compound that may prove useful in the treatment of HCMV replication.


Assuntos
Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Flavonoides/farmacologia , Rotenona/análogos & derivados , Replicação Viral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Viral , Flavonoides/química , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Rotenona/química , Rotenona/farmacologia , Internalização do Vírus/efeitos dos fármacos
10.
BMC Pharmacol Toxicol ; 19(1): 61, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30290834

RESUMO

BACKGROUND: Evaluating the toxicity or effectiveness of two or more toxicants in a specific population often requires specialized statistical software to calculate and compare median lethal doses (LD50s). Tests for equality of LD50s using probit regression with parallel slopes have been implemented in many software packages, while tests for cases of arbitrary slopes are not generally available. METHODS: In this study, we established probit-log(dose) regression models and solved them by the maximum likelihood method using Microsoft Excel. The z- and χ2-tests were used to assess significance and goodness of fit to the probit regression models, respectively. We calculated the lethal doses (LDs) of the toxicants at different significance levels and their 95% confidence limits (CLs) based on an accurate estimation of log(LD) variances. We further calculated lethal dose ratios and their 95% CLs for two examples without assuming parallel slopes following the method described by Robertson, et al., 2017. RESULTS: We selected representative toxicology datasets from the literature as case studies. For datasets without natural responses in the control group, the slopes, intercepts, χ2 statistics and LDs calculated using our method were identical to those calculated using Polo-Plus and SPSS software, and the 95% CLs of the lethal dose ratios between toxicants were close to those calculated using Polo-Plus. For datasets that included natural responses in the control group, our results were also close to those calculated using Polo-Plus and SPSS. CONCLUSION: This procedure yielded accurate estimates of lethal doses and 95% CLs at different significance levels as well as the lethal dose ratios and 95% CLs between two examples. The procedure could be used to assess differences in the toxicities of two examples without the assumption of parallelism between probit-log(dose) regression lines.


Assuntos
Relação Dose-Resposta a Droga , Modelos Estatísticos , Animais , Insetos/efeitos dos fármacos , Inseticidas/toxicidade , Dose Letal Mediana , Análise de Regressão , Rotenona/análogos & derivados , Rotenona/toxicidade
11.
J Cell Mol Med ; 22(12): 6213-6227, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30255595

RESUMO

Deguelin, a natural rotenoid isolated from several plants, has been reported to exert anti-tumour effects in various cancers. However, the molecular mechanism of this regulation remains to be fully elucidated. Here, we found that deguelin inhibited the growth of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo by downregulation of Bmi1 expression. Our data showed that Bmi1 is highly expressed in human NSCLC tissues and cell lines. Knockdown of Bmi1 significantly suppressed NSCLC cell proliferation and colony formation. Deguelin treatment attenuated the binding activity of Bmi1 to the Noxa promoter, thus resulting in Noxa transcription and apoptosis activation. Knockdown of Bmi1 promoted Noxa expression and enhanced deguelin-induced apoptosis, whereas overexpression of Bmi1 down-regulated Noxa protein level and deguelin-induced apoptosis. Overall, our study demonstrated a novel apoptotic mechanism for deguelin to exert its anti-tumour activity in NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína Quinase 7 Ativada por Mitógeno/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Rotenona/análogos & derivados , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos
12.
Exp Neurol ; 309: 67-78, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30076829

RESUMO

Mitochondrial dysfunction is considered as a critical mechanism in the pathogenesis of Parkinson's disease (PD). Increasing evidence supports the notion of mitochondria-associated membranes (MAMs) in mitochondrial dysfunction; yet little is known about the role of MAMs-related proteins in the pathogenesis of PD. Herein we exposed the nematode Caenorhabditis elegans to 0.5-10.0 µM rotenone (RO) or 0.2-1.6 mM paraquat (PQ) for 3 days. Our results showed that both RO and PQ induced similar Parkinsonism including motor deficits and dopaminergic degeneration. RO/PQ caused mitochondrial damages characterized by the increase of vacuole areas and autophagy vesicles, but the decrease of mitochondrial cristae. RO/PQ-impacted mitochondrial function was also demonstrated by the decrease of ATP level and mitochondrial membrane potential. Additionally, the attachment or surrounding of endoplasmic reticulum to the damaged mitochondria indicates ultrastructural alterations in MAMs. Using fluorescently labeled transgenic nematodes, we further found that the expression of tomm-7 and genes of Complex I, II and III was reduced, whereas the expression of pink-1 was increased in the exposed animals. To determine MAMs in toxicity toward PD, we investigated the mutants of hop-1 and pink-1, encoding presenilin and PTEN-induced putative kinase 1 (PINK1) in mitochondria-associated membranes, respectively. Results demonstrated that the mutation of both hop-1 and pink-1 reduced the vulnerability of lethal, behavioral, and mitochondrial toxicity induced by RO/PQ. These findings suggest that presenilin and PINK1 play important roles in the RO/PQ-induced neurotoxicity through the mechanisms involved in mitochondria-associated membranes.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Membrana/metabolismo , Doenças Mitocondriais/etiologia , Mutação/genética , Transtornos Parkinsonianos , Proteínas Serina-Treonina Quinases/genética , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Proteínas de Membrana/genética , Microscopia Eletrônica de Transmissão , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Movimento/efeitos dos fármacos , Movimento/fisiologia , Paraquat/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/patologia , Rotenona/análogos & derivados , Rotenona/toxicidade
13.
Cell Physiol Biochem ; 48(3): 1164-1176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30045011

RESUMO

BACKGROUND/AIMS: Deguelin is a natural rotenoid that shows anti-inflammatory and antimicrobial activities. Rotenoids prevent oxidative damage and potentiate natural antioxidant activity in diabetic conditions, suggesting utility in treating diabetes and its complications. Here, we evaluate the potential efficacy of deguelin against diabetic neuropathy (DN). METHODS: DN was induced by streptozotocin followed by daily treatment with deguelin (4, 6 or 8 mg/kg) for 14 days. Blood glucose was measured, neurobehavioral tests for nociception and motor coordination were performed, and neuron conduction velocities were analysed electrophysiologically. We also assessed (Na+-K+) ATPase activity, performed a reactive oxygen species assay, measured the levels of various markers of oxidative stress, and of hydrogen sulphide (H2S) in dorsal root ganglion (DRG) neurons, conducted immunoblotting studies for proteins and ELISA for inflammatory cytokines. RESULTS: Deguelin significantly suppressed mechanical and thermal hyperalgesia, as well as cold allodynia, and partially restored the conduction velocities of neurons in DN rats. Significantly decreased expression levels of capspase-3 in DRG neurons, and increased (Na+-K+) ATPase activity in sciatic nerves, were observed. In addition, deguelin decreased glucose levels, attenuated oxidative stress and neuroinflammation, and elevated levels of H2S, nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1, suggesting a disease-attenuating effect of deguelin in DN rats. To shed light on the underlying mechanism of action of deguelin, insulin- and dimethyl fumarate (BG-12)-treated groups were also included. Insulin suppressed glucose levels and BG-12 produced effects on Nrf2 levels similar to 8 mg/kg deguelin, confirming involvement of the Nrf2 pathway in the beneficial effects of deguelin against DN. CONCLUSIONS: Deguelin attenuated DN by decreasing oxidative stress and plasma glucose levels via the Nrf2 signalling pathway.


Assuntos
Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Rotenona/análogos & derivados , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/metabolismo , Masculino , Ratos Sprague-Dawley , Rotenona/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
14.
Cell Signal ; 50: 131-141, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30018008

RESUMO

Lung cancer is the leading cause of cancer-related death among both men and women every year, mainly due to metastasis. Although natural compound deguelin has been reported to inhibited cell migration and invasion in various cancer cells, the details of this regulation progress remain to be fully elucidated. In this study, we investigated the underlying mechanism of deguelin-suppressed metastasis of non-small cell lung cancer (NSCLC) cells. Our results demonstrate that deguelin inhibits NSCLC cell migration, invasion, and metastasis both in vitro and in vivo. These inhibitory effects of deguelin were mediated by suppressing of Cathepsin Z (CtsZ) expression and interrupting the interaction of CtsZ with integrin ß3. Moreover, deguelin inhibits the activation of CtsZ downstream FAK/Src/Paxillin signaling. Knockdown of CtsZ mimicked the effect of deguelin on NSCLC cells migration and invasion. Our study reveals that deguelin exerts its anti-metastatic effect both in vitro and in vivo is partly dependent on the suppression of CtsZ signaling. Deguelin would be a potential anti-metastasis agent against NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Catepsina Z/genética , Quinase 1 de Adesão Focal/genética , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Rotenona/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Rotenona/farmacologia , Transdução de Sinais/genética
15.
Cell Rep ; 23(1): 58-67, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29617673

RESUMO

A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten-/-;Trp53-/- fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo, deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI.


Assuntos
Antineoplásicos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Rotenona/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Complexo I de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/uso terapêutico , Fibroblastos/metabolismo , Glucose/metabolismo , Masculino , Camundongos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Rotenona/farmacologia , Rotenona/uso terapêutico , Proteína Supressora de Tumor p53/genética
16.
Int J Mol Med ; 41(6): 3157-3166, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512685

RESUMO

During the pathogenesis of gastric cancer, Akt signaling is considered as a pivotal inducer of gastric cancer development. Here we report the identification of anticancer activities of deguelin, a natural agent that inhibits Akt signaling. When applied to MGC-803 and MKN-45 cells, deguelin suppressed the proliferation and arrested cell cycle by p21-mediated inhibition of cyclin E. We further present in vitro evidence that deguelin promoted apoptosis of cancer cells by decreasing the phospho-Akt signaling and affecting expression of the apoptosis-associated genes Bax and Bcl-2. Additionally, deguelin was found to suppress the migration and invasion of gastric cancer cells. Taken together, these results indicated that deguelin exerted anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro.


Assuntos
Antineoplásicos/farmacologia , Rotenona/análogos & derivados , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo
17.
J Nat Prod ; 81(4): 1055-1059, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29442505

RESUMO

A concise and protecting-group-free total synthesis of the antiproliferative natural product (±)-deguelin (2) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu2O-mediated α-hydroxylation of deguelin (2) afforded tephrosin (3) in 90% yield.


Assuntos
Produtos Biológicos/química , Rotenona/análogos & derivados , Compostos de Vinila/química , Hidroxilação , Rotenona/química , Estereoisomerismo
18.
Microb Pathog ; 117: 93-99, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29432911

RESUMO

Acute lung injury (ALI), a devastating form of respiratory infections, is characterized by increased edema, release of cytokines, weakened arterial oxygenation and infiltration of neutrophils and lymphocytes. The objective of the research envisaged was to reveal protective effects of tephrosin (TP) in ALI. In the present investigation, sepsis was triggered in rats by cecal ligation and puncture (CLP) method, and TP was administered intraperitonially. Five groups - Group A (control), Group B (Sham group) Group C (infected and untreated), and Group D and E (infected and treated with 25 and 50 mg/kg TP respectively) - of ten rats each, were used for the investigation. Evaluation parameters included measurement of arterial oxygenation, lung water content, protein determination, cytokine determination, neutrophil and lymphocyte count in the bronchoalveolar lavage fluid (BALF). As indicated by histopathological examination, the lung injury score was maximum in group C, but indicated reduction in group D and E. Intracellular adhesion molecule (ICAM)-1 and macrophage inflammatory protein-2 (MIP-2) are known to be important mediators responsible for ALI. Reduction in the ICAM-1 and MIP-2 expression was found to reduce after treatment with TP. In comparison to group D, group E reflected higher magnitude of ICAM-1 and MIP-2 suppression due to administration of higher TP dose. Compared to Group A and B, Group E indicated slightly higher expression of ICAM-1 and MIP-2. The research envisaged thus supports that TP attenuates ICAM-1 and MIP-2 expression in sepsis induced ALI rat model.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Quimiocina CXCL2/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Rotenona/análogos & derivados , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Ceco/lesões , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/patologia , Contagem de Linfócitos , Masculino , Neutrófilos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Rotenona/administração & dosagem , Rotenona/farmacologia , Rotenona/uso terapêutico , Sepse/metabolismo
19.
Am J Chin Med ; 46(1): 209-229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29402127

RESUMO

Deguelin, a rotenoid, is isolated from a natural plant species, and has biological activities including antitumor function. In the present study, we investigated the effect of deguelin on the cell adhesion, migration and invasion of NCI-H292 human lung cancer cells in vitro. Cell viability was analyzed by using flow cytometer. Cell adhesion was determined by using the cell-matrix adhesion assay. Wound healing assay was used to examine cell migration. Cell migration and invasion were investigated using a Boyden chamber assay. The protein expression was measured by Western blotting and confocal laser microscopy. The electrophoretic mobility shift assay was used to measure NF-[Formula: see text]B p65 binding to DNA.We selected the concentrations of deguelin at 0, 0.5, 1.0, 1.5, 2.0 and 2.5[Formula: see text][Formula: see text]M and we found that those concentrations of deguelin did not induce significant cytotoxic effects on NCI-H292 cells. Thus, we selected those concentrations of deguelin for metastasis assay. We found that deguelin inhibited cell adhesion, migration and invasion in dose-dependent manners that was assayed by wound healing and transwell methods, respectively. Deguelin decreased the expression of MMP-2/-9, SOS 1, Rho A, p-AKT (Thr308), p-ERK1/2, p-p38, p-JNK, NF-[Formula: see text]B (p65) and uPA in NCI-H292 cells. Deguelin suppressed the expression of PI3K, SOS 1, NF-[Formula: see text]B (p65), but did not significantly affect PKC and Ras in the nuclei of NCI-H292 cells that were confirmed by confocal laser microscopy. We suggest that deguelin may be used as a novel anticancer metastasis of lung cancer in the future.


Assuntos
Antineoplásicos Fitogênicos , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Pulmonares/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Rotenona/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/genética , Rotenona/isolamento & purificação , Rotenona/farmacologia
20.
Mol Cell Biochem ; 442(1-2): 177-186, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29030732

RESUMO

As a natural agent for chemotherapy, deguelin remarkably suppresses proliferation in numerous solid cancers. Nevertheless, the molecular mechanisms of its suppression are still insufficient. In our research, it was revealed that deguelin induced cell death of lung cancer cells (LCCs) by triggering expression of PUMA. Deguelin triggered PUMA induction independently of p53 via suppression of PI3K/AKT pathway, therefore stimulating Foxo3a to bind with PUMA promoter and stimulate its transcription. Subsequent to activation, PUMA motivated Bax as well as the intrinsic mitochondrial cell death pathway. Removal of PUMA from LCC cells led to deguelin resistance, suggesting deguelin-induced cell death was modulated by PUMA. Furthermore, we demonstrated that deguelin enhanced the chemotherapeutic sensitivity of doxorubicin in vitro and in vivo, which were associated with potentiated PUMA induction. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of deguelin in lung cancer cells and provide the rationale for clinical evaluation.


Assuntos
Proteínas Reguladoras de Apoptose/sangue , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/sangue , Rotenona/análogos & derivados , Células A549 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Rotenona/farmacologia
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