RESUMO
Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of ß-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for cancer treatment as antimicrotubule agent.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Tubulina (Proteína)/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Moduladores de Tubulina/química , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/química , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Relação Estrutura-Atividade , ApoptoseRESUMO
Nine new isomalabaricane terpenoids (1-9) were isolated from the sponge Rhabdastrella globostellata of Ximao Island, together with 13 known ones (10-22). The structures were established by spectroscopic data interpretation and chemical calculations, as well as by comparison with spectroscopic data of known compounds. Notably, of the new isolates, hainanstelletin A (5) is the first representative of a nitrogenous isomalabaricane. The isolated compounds were evaluated against several cancer cell lines and two bacterial pathogens. In addition, moderate to strong antibacterial activities against Streptococcus pyogenes were also detected among geometric isomers 1, 2, and 10-12, with minimum inhibitory concentrations of 0.1-1.8 µg/mL.
Assuntos
Antineoplásicos , Poríferos , Triterpenos , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Terpenos/farmacologia , Triterpenos/químicaRESUMO
The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Janus Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/antagonistas & inibidores , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/farmacologia , Janus Quinases/metabolismo , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores 5-HT4 de Serotonina/genética , Fator de Transcrição STAT3/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis; thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial-mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.
Assuntos
Alginatos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Alginatos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Organismos Aquáticos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide , Avaliação Pré-Clínica de Medicamentos , Transição Epitelial-Mesenquimal , Humanos , Laminaria/química , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/patologia , Camundongos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/patologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Different cancer chemopreventive agents may act synergistically and their combination may produce enhanced protective effects against carcinogenesis than each individual agent alone. Herein, we investigated the chemopreventive effects of nobiletin (NBT, a citrus polymethoxyflavone) and atorvastatin (ATST, a lipid-lowering drug) in colon cancer cells/macrophages and an azoxymethane (AOM)-induced colon carcinogenesis rat model. The results demonstrated that co-treatments of NBT/ATST produced enhanced growth inhibitory and anti-inflammatory effects on the colon cancer cells and macrophages, respectively. Isobologram analysis confirmed that these interactions between NBT and ATST were synergistic. NBT/ATST co-treatment also synergistically induced extensive cell cycle arrest and apoptosis in colon cancer cells. Oral administration of NBT (0.1%, w/w in diet) or ATST (0.04%, w/w in diet) significantly decreased colonic tumor incidence and multiplicity in AOM-treated rats. Most importantly, co-treatment of NBT/ATST at their half doses (0.05% NBT + 0.02% ATST, w/w in diet) resulted in even stronger inhibitory effects on colonic tumor incidence and multiplicity than did NBT or ATST alone at higher doses. Statistical analysis confirmed that the enhanced chemopreventive activities against colon carcinogenesis in rats by the NBT/ATST combination were highly synergistic. Our results further demonstrated that NBT/ATST co-treatment profoundly modulated key cellular signaling regulators associated with inflammation, cell proliferation, cell cycle progression, apoptosis, angiogenesis and metastasis in the colon of AOM-treated rats. In conclusion, for the first time, our results demonstrated a strong synergy in inhibiting colon carcinogenesis produced by the co-treatment of NBT and ATST, which provided a scientific basis for using NBT in combination with ATST for colon cancer chemoprevention in humans.
Assuntos
Anticarcinógenos/farmacologia , Atorvastatina/farmacologia , Carcinogênese/efeitos dos fármacos , Colo/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Flavonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Azoximetano/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioprevenção/métodos , Colo/patologia , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Células HT29 , Humanos , Masculino , Camundongos , Ratos , Ratos Endogâmicos F344RESUMO
BACKGROUND: Norcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study. METHODS: Two human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho-EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis. RESULTS: NCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment. CONCLUSIONS: NCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients.
Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Receptores ErbB/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Gefitinibe , Células HCT116 , Células HT29 , Humanos , Quinazolinas/farmacologiaRESUMO
Marine sulfated polysaccharide (MSP) is a natural high molecular polysaccharide containing sulfate groups, which widely exists in various marine organisms. The sources determine structural variabilities of MSPs which have high security and wide biological activities, such as anticoagulation, antitumor, antivirus, immune regulation, regulation of glucose and lipid metabolism, antioxidant, etc. Due to the structural similarities between MSP and endogenous heparan sulfate, a majority of studies have shown that MSP can be used to treat diabetic nephropathy (DN) in vivo and in vitro. In this paper, we reviewed the anti-DN activities, the dominant mechanisms and structure-activity relationship of MSPs in order to provide the overall scene of MSPs as a modality of treating DN.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Sulfatos/química , Nefropatias Diabéticas/tratamento farmacológico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Polissacarídeos/química , Heparitina Sulfato , Organismos Aquáticos/química , AntioxidantesRESUMO
Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed.
Assuntos
Apoptose , Proliferação de Células , Dissulfetos , Inibidores de Histona Desacetilases , Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Dissulfetos/química , Dissulfetos/farmacologia , Dissulfetos/síntese química , Humanos , Apoptose/efeitos dos fármacos , Histona Desacetilases/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Tirosina/análogos & derivadosRESUMO
P-selectin has been shown to enhance growth and metastasis of mouse tumors by promoting regulatory T cell (Treg) infiltration into the tumors. Theoretically, a P-selectin antagonist could suppress the process. Popylene glycol alginate sodium sulfate (PSS) is a heparin-like marine drug, which was originally approved to treat cardiovascular disease in China. Previously, we reported that PSS was an effective P-selectin antagonist in vitro. However, it is unknown whether PSS can regulate Treg infiltration and its effect on lung metastasis in vivo. Our results showed that PSS at 30â¯mg/kg significantly suppressed lung metastasis and improved overall survival, with potency comparable to the positive control LMWH. Mechanistic study indicated that PSS blocked tumor cells adhesion and activated platelets by directly binding with activated platelet's P-selectin. Compared to the model group, PSS decreased the percent of Tregs by 63â¯% in lungs after treating for 21â¯days while increasing CD8+ T cells (1.59-fold) and Granzyme B+ CD8 T cells (2.08-fold)' percentage for generating an adaptive response for systemic tumor suppression. The study indicated that the P-selectin antagonist, PSS, suppressed lung metastasis by inhibiting the infiltration of regulatory T cells (Treg) into the tumors.
RESUMO
The effect of selenium compounds on extracellular redox modulating capacity was studied in murine macrophage RAW 264.7 cells and differentiated human THP-1 monocytes. The arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe), and ebselen were capable of inducing extracellular cysteine accumulation via a cystine- and glucose-dependent process. Extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc(-) transporter), supporting the involvement of Xc(-) transporter for cystine uptake in the above process. These arylselenium compounds also induced cellular thioredoxin reductase (TrxR) expression, particularly at the exofacial surface of cells. TrxR1 knockdown using small interfering RNA attenuated TrxR increases and cysteine efflux induced in cells by DPDSe. Sodium selenite (Na2SeO3), selenomethionine (SeMet), seleno-l-cystine (SeCySS), and Se-methylselenocysteine (MeSeCys) did not have these effects on macrophages under the same treatment conditions. The effects of organoselenium compounds on extracellular redox may contribute to the known, but inadequately understood, biological effects of selenium compounds.
Assuntos
Cisteína/metabolismo , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Compostos Organosselênicos/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Monócitos/citologia , Monócitos/metabolismo , Oxirredução/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/análiseRESUMO
Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50 of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities.
Assuntos
Curcumina/análogos & derivados , Desenho de Fármacos , Receptores ErbB/metabolismo , Pirimidinas/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Curcumina/síntese química , Curcumina/farmacologia , Receptores ErbB/antagonistas & inibidores , Células HCT116 , Células HT29 , Humanos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Numerous disseminated tumor cells specifically overexpress P-selectin. Therefore, it was thought to be a potential target for tumor therapy. Herein, we described a novel P-selectin-targeted glycosyl ligand-sulfated polyguluronic acid (PGS), as an oriented carrier of P-selectin-targeted drug delivery system. Specifically, the PGS-SS-DOX polymeric micelles were constructed to confirm the practicability of the PGS carrier as a new P-selectin-targeted ligand. PGS-SS-DOX micelles comprised P-selectin-targeted PGS, doxorubicin (DOX) as an anticarcinogen, and pH/redox dual-sensitive bio-linker facilitating drug release in tumor tissues. In vitro and in vivo data showed that PGS-SS-DOX micelles significantly increased tumor cell killing capacity and exhibited a favorable biocompatibility comparison with Free-DOX. This work proved that PGS was an ideal low immunogenic, biodegradable drug carrier for the delivery of anti-cancer drugs. The facile PGS-SS-drug micelle system provided enormous opportunities for treating disseminated tumors utilizing many irreplaceable anticarcinogens.
Assuntos
Antineoplásicos , Micelas , Selectina-P , Sulfatos , Ligantes , Sistemas de Liberação de Medicamentos , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Polímeros , Portadores de Fármacos , Concentração de Íons de Hidrogênio , Liberação Controlada de FármacosRESUMO
Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability. In addition, centipede peptides generally have novel structures and high potency and specificity and therefore hold great promise both as diagnostic tools and in the treatment of human disease. Here, we review the centipede peptide toxins with reported effects on ion channels, including Nav, Kv, Cav and the nonselective cation channel polymodal transient receptor potential vanilloid 1 (TRPV1).
Assuntos
Proteínas de Artrópodes/farmacologia , Venenos de Artrópodes/farmacologia , Mordeduras e Picadas/metabolismo , Quilópodes/metabolismo , Descoberta de Drogas , Canais Iônicos/efeitos dos fármacos , Moduladores de Transporte de Membrana/farmacologia , Animais , Proteínas de Artrópodes/metabolismo , Venenos de Artrópodes/metabolismo , Humanos , Canais Iônicos/metabolismo , Moduladores de Transporte de Membrana/metabolismo , Conformação Proteica , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Polysaccharides have aroused considerable interest due to their diverse biological activities and low toxicity. In this study, we evaluated the effect of marine polysaccharide sulfated polymannuroguluronate (TGC161) on the leukopenia induced by chemotherapy. It is found that TGC161 ameliorates the leukopenia. Besides, TGC161 would promote CD4+ T cell differentiation and maturation in the thymus, but does not have a significant effect on precursor cells in bone marrow. Furthermore, TGC161 inhibits CD4+ T cell apoptosis in vitro. Collectively, our findings offer a natural and harmless polysaccharide to ameliorate leukopenia.
Assuntos
Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Leucopenia/prevenção & controle , Polissacarídeos/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Leucopenia/imunologia , Leucopenia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) has been widely used as an approach worldwide. Chinese Medicines (CMs) had been used to treat and prevent viral infection pneumonia diseases for thousands of years and had accumulated a large number of clinical experiences and effective prescriptions. AIM OF THE STUDY: This research aimed to systematically excavate the classical prescriptions of Chinese Medicine (CM), which have been used to prevent and treat Pestilence (Wenbing, Wenyi, Shiyi or Yibing) for long history in China, to obtain the potential prescriptions and ingredients to alternatively treat COVID-19. MATERIALS AND METHODS: We developed the screening system based on data mining, molecular docking and network pharmacology. Data mining and association network were used to mine the high-frequency herbs and formulas from ancient prescriptions. Virtual screening for the effective components of high frequency CMs and compatibility Chinese Medicine was explored by a molecular docking approach. Furthermore, network pharmacology method was used to preliminarily uncover the molecule mechanism. RESULTS: 574 prescriptions were obtained from 96,606 classical prescriptions with the key words to treat "Warm diseases (Wenbing)", "Pestilence (Wenyi or Yibing)" or "Epidemic diseases (Shiyi)". Meanwhile, 40 kinds of CMs, 36 CMs-pairs, 6 triple-CMs-groups existed with high frequency among the 574 prescriptions. Additionally, the key targets of SARS-COV-2, namely 3CL hydrolase (Mpro) and angiotensin-converting enzyme 2(ACE2), were used to dock the main ingredients from the 40 kinds by the LigandFitDock method. A total of 66 compounds components with higher frequency were docked with the COVID-19 targets, which were distributed in 26 kinds of CMs, among which Gancao (Glycyrrhizae Radix Et Rhizoma), HuangQin (Scutellariae Radix), Dahuang (Rhei Radix Et Rhizome) and Chaihu (Bupleuri Radix) contain more potential compounds. Network pharmacology results showed that Gancao (Glycyrrhizae Radix Et Rhizoma) and HuangQin (Scutellariae Radix) CMs-pairs could also interact with the targets involving in immune and inflammation diseases. CONCLUSIONS: These results we obtained probably provided potential candidate CMs formulas or active ingredients to overcome COVID-19. Prospectively, animal experiment and rigorous clinic studies are needed to confirm the potential preventive and treat effect of these CMs and compounds.
Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/tratamento farmacológico , COVID-19 , Infecções por Coronavirus/virologia , Mineração de Dados , Humanos , Modelos Moleculares , Pandemias , Extratos Vegetais , Pneumonia Viral/virologia , Conformação Proteica , SARS-CoV-2 , Proteínas ViraisRESUMO
Nobiletin (NBT), a citrus flavonoid, has been associated with various health benefits. Herein, we investigated the chemopreventive actions of NBT and its metabolites in a pulmonary carcinogenesis mouse model and human lung cancer cells. In 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-treated mice, the oral administration of NBT significantly suppressed lung tumorigenesis as evidenced by reduced tumor volume compared to the control mice. NBT also greatly attenuated cell proliferation in the lung of NNK-treated mice. Our previous study has identified three major metabolites of NBT, namely, 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3). In this study, we further determined the inhibitory effects of NBT and its metabolites on human non-small cell lung cancer (NSCLC) cells and the underlying mechanisms of action. Interestingly, we found that M2 and M3 exerted much stronger growth inhibition on both H460 and H1299 cells, compared to their parent compound NBT. Flow cytometry and western blotting analysis revealed that M2 and M3 caused significant cell cycle arrest and cellular apoptosis and profoundly modulated multiple proteins associated with cell proliferation and cell death, including p21, cyclin B1, CDK1, cyclin D1, CDK6, CDK4, Bax, cleaved caspase-1, and cleaved PARP. Overall, our results demonstrated that the oral administration of NBT significantly inhibited lung carcinogenesis in mice, and these chemopreventive effects could be attributed to its metabolites that showed potent anti-cancer effects.
Assuntos
Antioxidantes/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Flavonas/farmacologia , Neoplasias Experimentais/induzido quimicamente , Animais , Antioxidantes/metabolismo , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Flavonas/metabolismo , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Nitrosaminas/toxicidadeRESUMO
Naturally occurring constrained peptides are frequently used as scaffolds for bioactive peptide grating due to their high stability. Here, we used in silico methods to design several constrained peptides comprising a scorpion toxin scaffold, a MDM2 binding epitope, and a cluster of positively charged residues. The designed peptides displayed varied binding affinity to MDM2 despite differing by only one or two residues. One of the peptides, SC426, had nanomolar binding affinity (KD =6.6±2.6â nm) to MDM2, and exhibited stronger inhibitory activity on the proliferation of HCT116 cells (p53-wild type) and SW480 cells (p53-mutant) than that of nutlin-3a. Binding mode analysis of the designed peptide at MDM2 suggests that the conserved "FWL" epitope was buried in the hydrophobic binding pocket, and the residues located at the periphery of the binding site contributed to the high binding affinity of SC426. Overall, in silico design of miniproteins with therapeutic potential through epitope grafting to the naturally occurring constrained peptide is an effective strategy.
Assuntos
Antineoplásicos/química , Peptídeos/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/farmacologia , Peptídeos/farmacologia , Piperazinas/farmacologiaRESUMO
Selectins dominate the formation of the metastasis niche and are considered important targets for exploring antimetastatic drugs. In this study, we evaluated the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) and a series of PSS derivatives on P-, L- or E-selectin-mediated binding with tumor cells. We found that PSS effectively prevented the binding of P- or L-selectin with tumor cells. Moreover, the structure-activity relationship study indicated that the activity of PSS is related to the sulfate group at the C-2/C-3 position, the propylene glycol substituent at the C-6 position, the ratio of guluronic acid to mannuronic acid, and the molecular weight. Additionally, PSS derivatives significantly suppressed lung metastasis in vivo. Our results demonstrated that PSS and its derivatives are potential antimetastatic drugs candidates.
Assuntos
Alginatos/química , Alginatos/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Selectinas/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Peso Molecular , Metástase Neoplásica , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Combining different chemopreventive agents is a promising strategy to reduce cancer incidence and mortality due to potential synergistic interactions between these agents. Previously, we demonstrated that oral administration of nobiletin (NBT, a citrus flavonoid) at 0.05% (w/w, in diet) together with atorvastatin (ATST, a lipid-lowering drug) at 0.02% (w/w, in diet) produced much stronger inhibition against colon carcinogenesis in rats in comparison with that produced by NBT (at 0.1% w/w in diet) or ATST (at 0.04% w/w in diet) alone at higher doses. To further elucidate the mechanism of this promising synergy between NBT and ATST, herein, we measured the levels of NBT, its major metabolites and ATST in the colonic tissue of rats fed NBT (0.05% w/w, in diet) + ATST (0.02% w/w, in diet), and determined the mode of interaction between the major NBT metabolite and ATST in inhibiting colon cancer cell growth. HPLC-MS analysis showed that 4'-demethylnobiletin (4DN) is the most abundant metabolite of NBT with a level about 5-fold as high as that of NBT in the colonic tissue, which indicated the potential significance of 4DN in mediating the biological effects of NBT in the colon. We found that co-treatments of 4DN/ATST at 2 : 1 concentration ratio produced much stronger growth inhibitory effects on human colon cancer HT-29 cells than 4DN or ATST alone, and isobologram analysis confirmed that this enhanced inhibitory effect by the 4DN/ATST combination was highly synergistic. The co-treatment of 4DN/ATST led to G0/G1 cell cycle arrest and induced extensive apoptosis in HT-29 cells. Furthermore, the 4DN/ATST co-treatment profoundly modulated key signaling proteins related to the regulation of the cell cycle and apoptosis. Our results demonstrated a strong synergy produced by the 4DN/ATST co-treatment in inhibiting colon cancer cell growth, which provided a novel mechanism by which NBT/ATST in combination synergistically inhibit colon carcinogenesis.
Assuntos
Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Atorvastatina/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Flavonas/administração & dosagem , Flavonas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Animais , Anticarcinógenos/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Sinergismo Farmacológico , Células HT29 , Humanos , Estrutura Molecular , Ratos , Ratos Endogâmicos F344RESUMO
5-Demethyltengeretin (5DT) is a citrus flavonoid with various potential health benefits. To provide physiologically relevant information on the anti-inflammatory properties of 5DT, we identified the major metabolite of 5DT in the mouse colon and established its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. CD-1 mice were fed with a 5DT-containing diet for four weeks, and colonic mucosa samples were collected and subjected to LC-MS analysis. Xanthomicrol (XAN) was identified as the major metabolite of 5DT in the mouse colon. More importantly, the colonic level of XAN was about 3.1-fold higher than that of 5DT. The anti-inflammatory effects of 5DT and XAN were determined in LPS-stimulated macrophages. XAN produced significant inhibitory effects on the production of nitric oxide and PGE2. Western blotting and real-time PCR analyses demonstrated that XAN greatly decreased the protein and mRNA levels of iNOS as well as the protein level of COX-2. Furthermore, XAN also reduced the production of pro-inflammatory cytokine IL-1ß and induced the expression of anti-oxidative enzyme HO-1. CONCLUSION: Our results demonstrated that XAN is a major metabolite of 5DT in the colon of mice fed with 5DT, and XAN may play important roles in the anti-inflammatory effects elicited by orally administered 5DT.