RESUMO
Quinoline derivatives have been reported to possess a wide range of pharmaceutical activities. Our group previously synthesized a series of quinoline compounds, in which compound 91b1 showed a significant anticancer effect. The purpose of this study was to evaluate the anticancer activity of compound 91b1 in vitro and in vivo, and screen out its regulated target. A series of cancer cell lines and nontumor cell lines were treated with compound 91b1 by MTS cytotoxicity assay and cell-cycle assay. In vivo anticancer activity was evaluated by a xenografted model on nude mice. Target prediction of 91b1 was assessed by microarray assay and confirmed by pancancer analysis. Relative expression of the target gene Lumican was measured by qRT-PCR. 91b1 significantly reduced tumor size in the nude mice xenograft model. Lumican was downregulated after 91b1 treatment. Lumican was proven to increase tumorigenesis in vivo, as well as cancer cell migration, invasion, and proliferation in vitro. The results of this study suggest that the anticancer activity of compound 91b1 probably works through downregulating the gene Lumican.
Assuntos
Antineoplásicos , Quinolinas , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Lumicana/efeitos dos fármacos , Lumicana/metabolismo , Camundongos Nus , Quinolinas/farmacologiaRESUMO
A palladium-catalyzed C-N bond coupling reaction between arylhydrazines and aryl tosylates for facile synthesis of unsymmetrical N,N-diarylhydrazines has been developed. Employing the catalyst system of Pd(TFA)2 associated with newly developed phosphine ligand L1, the monoarylation of arylhydrazine proceeds smoothly to afford desired products in good-to-excellent yields (up to 95%) with good functional group compatibility. This method provides an alternative synthetic pathway for accessing structurally diversified N,N-diarylhydrazines from simple and easily accessible coupling components.
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Tandem reactions of Pd-catalyzed cross-coupling of 3-(2-isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich-type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich-type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich-type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.
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This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.
Assuntos
Antibacterianos/farmacologia , Oxiquinolina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxiquinolina/síntese química , Oxiquinolina/química , Relação Estrutura-AtividadeRESUMO
Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos de Linfócitos T , Imunoterapia Adotiva , Linfócitos T , Antígenos de Neoplasias , Microambiente TumoralRESUMO
Combinations of crude rhizomes of Coptis chinensis Franch., Ranunculaceae, and fruits of Evodia rutaecarpa (Juss.) Benth., Rutaceae, at a ratio of 6 : 1 (formula A) and 1 : 6 (formula B) were extracted with boiling water, and their modulatory activity on enteric mucosal immune responses in mice with dextran sulphate sodium-induced ulcerative colitis was investigated. The results showed that both formulas could reduce the severity of inflammation in the colon. Formula A at a low dose can decrease myeloperoxidase (MPO) activity, and formula B was inactive. Both formulas did not affect the percentages of CD4 (+) and CD8 (+) T cells in the periphery, but they evoked an increase of CD8 (+) T cells among the enteric intraepithelial lymphocytes. Formula B at a low dose could increase both CD4 (+) and CD8 (+) cells, and formula A at a high dose could only increase CD8 (+) T cells among the Peyer's patch lymphocytes (p < 0.05). Both formulas did not affect the percentages of CD4 (+) and CD8 (+) T cells among the lamina propria lymphocytes, but decreased the serum concentration of IL-1 beta (p < 0.05 at a low dose of formula A) and enhanced the level of IL-10 in serum (p < 0.05 at a low dose formula B). We conclude that both formulas have a similar modulating effect on enteric mucosal immune responses, the major difference being that formula A could decrease the level of IL-1 beta, while formula B could increase the IL-10 dose in serum.
Assuntos
Colite Ulcerativa/induzido quimicamente , Sulfato de Dextrana/toxicidade , Imunidade nas Mucosas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ranunculaceae/química , Rutaceae/química , Animais , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.
Assuntos
Antineoplásicos/síntese química , Óxidos/síntese química , Fosfinas/síntese química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Óxidos/uso terapêutico , Fosfinas/uso terapêuticoRESUMO
Multidrug resistance (MDR) is one of conventional cancer chemotherapy's limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a's MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a's inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a's MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.
RESUMO
Phthalic anhydride is a highly toxic substance, facing, however, the problem of hydrolysis. In fact, it is rapidly hydrolyzed in aqueous medium, generating phthalic acid as the final product, which is almost harmless to viable cells. Here we describe the 'one pot' condensation reaction for the synthesis of phthalic imide derivative (benzothiazole containing phthalimide), exhibiting in vitro cytotoxic potential on human cancer cell lines. We further demonstrated that both caspase-dependent and -independent pathways are involved in our novel benzothiazole containing phthalimide induced apoptosis on cancer cells.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzotiazóis/química , Carcinoma/patologia , Ftalimidas/síntese química , Ftalimidas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Fenômenos Químicos , Físico-Química , Humanos , Estrutura Molecular , Ftalimidas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of novel oxoisoaporphine alkaloid derivatives, 9-aminoalkanamido-1-azabenzanthrone (general formula Ar-NHCO(CH(2))(n)NR(2), Ar=1-azabenzanthrone, n=1, 2 or 3), had been synthesized. Compared with 1-azabenzanthrone, the derivatives had significantly higher DNA binding affinity with calf thymus DNA, and higher potent cytotoxicity against different tumor cell lines. The cytotoxicity and the structure-activity relationship of the prepared compounds were studied. The derivatives with two methylene groups (n=2), and piperidine or ethanolamine functional group in the side chain exhibited highest DNA binding affinity and cytotoxicity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Aporfinas/síntese química , Aporfinas/farmacologia , DNA/química , Animais , Antineoplásicos/química , Aporfinas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
The aim of the study was to develop and evaluate a new method for the production of puerarin phospholipids complex (PPC) microparticles. The advanced particle formation method, solution enhanced dispersion by supercritical fluids (SEDS), was used for the preparation of puerarin (Pur), phospholipids (PC) and their complex particles for the first time. Evaluation of the processing variables on PPC particle characteristics was also conducted. The processing variables included temperature, pressure, solution concentration, the flow rate of supercritical carbon dioxide (SC-CO2) and the relative flow rate of drug solution to CO2. The morphology, particle size and size distribution of the particles were determined. Meanwhile Pur and phospholipids were separately prepared by gas antisolvent precipitation (GAS) method and solid characterization of particles by the two supercritical methods was also compared. Pur formed by GAS was more orderly, purer crystal, whereas amorphous Pur particles between 0.5 and 1microm were formed by SEDS. The complex was successfully obtained by SEDS exhibiting amorphous, partially agglomerated spheres comprised of particles sized only about 1microm. SEDS method may be useful for the processing of other pharmaceutical preparations besides phospholipids complex particles. Furthermore adopting a GAS process to recrystallize pharmaceuticals will provide a highly versatile methodology to generate new polymorphs of drugs in addition to conventional techniques.
Assuntos
Isoflavonas/química , Fosfolipídeos/química , Tecnologia Farmacêutica/métodos , Dióxido de Carbono/química , Precipitação Química , Química Farmacêutica , Cristalização , Tamanho da Partícula , Pressão , Soluções , Solventes/química , TemperaturaRESUMO
Cisplatin (CDDP) is one of the front-line chemotherapeutic drugs used in the treatment of esophageal squamous cell carcinoma (ESCC). Occurrence of resistance to CDDP has become one of the main challenges in cancer therapy. In this study, the gene expression profile of CDDP-resistant ESCC cells was investigated and molecular approaches were explored in an attempt to reverse the CDDP resistance. A CDDP-resistant SLMT-1/CDDP1R cell line was established from SLMT-1 cells by subculturing in the medium containing an increasing concentration of CDDP (0.1â»1µg/mL). Mitochondrial (MTS) cytotoxicity assay, cell proliferation assay and cell morphology were used to assess the acquisition of cisplatin-resistance. The most differentially expressed gene in SLMT-1/CDDP1R cells was identified by cDNA microarray analysis compared with the parental SLMT-1 cells and validated by quantitative real-time polymerase chain reaction (qPCR). Association between expression of the most differentially expressed target gene to cisplatin-resistance was verified by RNA interference. An attempt to reversecisplatin-resistance phenotypes was made by using the vector expressing the most downregulated target gene in the CDDP-resistant cells. A CDDP-resistant ESCC cell line, SLMT-1/CDDP1R, was established with 2.8-fold increase CDDP-resistance (MTS50 = 25.8 µg/mL) compared with the parental SLMT-1 cells. cDNA microarray analysis revealed that IGFBP5 showed the highest level of downregulation in SLMT-1/CDDP1R cells compared with the parental SLMT-1 cells. Suppression of IGFBP5 mediated by IGFBP5-targeting siRNA in parental SLMT-1 cells confirmed that IGFBP5 suppression in ESCC cells would induce CDDP-resistance. More importantly, upregulation of IGFBP5 using IGFBP5 expression vector reduced cisplatin-resistance in SLMT-1/CDDP1R cells by 41%. Thus, our results demonstrated that IGFBP5 suppression is one of the mechanisms for the acquisition of cisplatin-resistance in ESCC cells. Cisplatin-resistance phenotype can be reversed by increasing the expression level of IGFBP5. The overall findings of this study thus offered a new direction for reversing the CDDP resistance in ESCC and possibly in other cancer types with further investigations in future.
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Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.
RESUMO
Stabilization of G-quadruplex structures in the promoter region of certain oncogenes is an emerging field in anticancer drug design. Human c-myc gene is one of these oncogenes, and G-quadruplexes have been proven to be the transcriptional controller of this gene. In the present study, the interaction of quindoline derivatives with G-quadruplexes in c-myc was investigated. The experimental results indicated that these derivatives have the ability to induce/stabilize the G-quadruplexes in c-myc, which lead to down-regulation of the c-myc in the Hep G2 cell line. It was found that derivatives with terminal amino groups in their side chains would selectively bind to the isomers with the double nucleotide loops in the absence of K+. Molecular modeling studies revealed the binding mode between the derivatives and the G-quadruplexes is end-stacking at the 3'-position, and the positively charged side chain on the quindoline derivatives may contribute to the selectivity to certain loop isomers of topological quadruplexes as well as the improved stabilization action.
Assuntos
Alcaloides/química , Antineoplásicos/química , DNA/genética , Guanina/química , Indóis/química , Conformação de Ácido Nucleico , Proteínas Proto-Oncogênicas c-myc/biossíntese , Quinolinas/química , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , DNA/química , Diálise , Humanos , Indóis/farmacologia , Isomerismo , Modelos Moleculares , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Quinolinas/farmacologia , Eletricidade Estática , Relação Estrutura-Atividade , TermodinâmicaRESUMO
There are several scientific approaches for the determination of cellular growth influences of known or novel substances under in vitro conditions, among which colourimetric absorption measurement is considered to be one of the convenient methods. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay is one of the commonly used colourimetric absorption assays based on the ability of dehydrogenase from viable cells to produce the brown soluble formazan detectable at 490 nm. Here we have tested the possible growth influence of iron (II) sulphate on two human cancer cell lines, the K562 chronic myelogenous leukaemia and T47D breast carcinoma cells, based on the MTS assay. We found that iron (II) sulphate possessed an inhibitory effect when added at 16- to 125-microM concentrations, but iron (II) sulphate became growth stimulatory when its concentration was further increased to 1000 microM. In addition, a dose-dependent increase in absorbance at the same wavelength was observed when we repeated the experiments without the addition of MTS and phenazine methosulfate. When we further repeated the cell growth determinations using adenosine triphosphate content assay for K562 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for T47D, iron (II) sulphate showed a consistent dose-dependent growth inhibitory effect. Morphological investigation after methylene blue staining clearly demonstrated that iron (II) sulphate, at a concentration of 1000 microM, is cytotoxic to T47D cells. Interestingly, a consistent increment for the absorbance at 490 nm was further observed with increased iron (II) sulphate concentration either in the presence or absence of MTS even in a cell-free environment. Thus we conclude that iron (II) sulphate is actually growth inhibitory and even cytotoxic at high concentrations towards the K562 and T47D cancer cells and the paradoxical proliferative activity of iron (II) sulphate on these two cancer cell lines using the MTS assay was solely due to the oxidation of initial pale green iron (II) to brownish iron (III) during incubation in the aqueous condition.
Assuntos
Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Compostos de Ferro/farmacologia , Neoplasias/patologia , Sulfatos/farmacologia , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Neoplasias da Mama/patologia , Carcinoma/patologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células Tumorais CultivadasRESUMO
PURPOSE: 83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis. MATERIALS AND METHODS: A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2-derived prostaglandin E2 (PGE2) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450. RESULTS: 83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2-derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft. CONCLUSION: The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Humanos , Ligantes , Camundongos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Quinolinas/síntese química , Quinolinas/química , RNA Mensageiro , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chinese practitioners have employed the use of traditional Chinese medicine as an anti-cancer agent since the ancient period. Different combinations have been formulated for various purposes. Some have been claimed for post-chemotherapy use but their direct actions on cancer cells may not be significantly reported. In the present study, we have tested the possible anti-leukemia potential of a combination regimen including crocodile egg extract, wild radix ginseng and natural Ganoderma lucidum (CGG extract) on acute myelogenous leukemia (AML) in vitro. A water soluble CGG extract was prepared and its antiproliferative activity was tested on the KG1a AML cell line and two freshly prepared bone marrow aspirate samples isolated from patients with de novo AML during presentation by a MTS/PMS assay. Furthermore, the possible activity of the CGG extract on the regeneration potential of KG1a cells was also investigated using a semi-solid methyl-cellulose colony formation assay. Lastly, the acute toxicity of CGG extract was further examined by a single high-dose oral feeding to rats. We found that the CGG extract could possess significant antiproliferative activity on AML cells. A strong colony formation inhibition was further demonstrated on KG1a cells. After feeding the rats with an excessive dose of CGG extract, we observed no development of acute toxicity. We concluded that the CGG extract has growth inhibitory potential on KG1a cells and AML bone marrow samples in vitro. An in vivo toxicity test revealed that no acute toxicity was observed after feeding the rats a high dosage of the CGG extract. Further animal model tests are necessary to investigate the possible chronic toxicity of the CGG extract.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Jacarés e Crocodilos , Animais , Células da Medula Óssea/efeitos dos fármacos , Extratos Celulares , Linhagem Celular Tumoral , Ovos , Humanos , Masculino , Panax/química , Fitoterapia , Preparações de Plantas/farmacologia , Ratos , Reishi/químicaRESUMO
Hypercholesterolemia is a dominant risk factor for the development and progression of atherosclerosis and cardiovascular diseases. Natural compounds have been proved to be useful in lowering serum cholesterol to slow down the progression of cardiovascular diseases. Pueraria lobata is employed clinically to treat cardiovascular diseases in China. In the present study, the atheroscleroprotective potential of the herb's major active compound, puerarin, was investigated by monitoring serum lipid profile and major enzyme expressions on cholesterol homeostasis in Sprague-Dawley rats fed with control diet, hypercholesterolmic diet or hypercholesterolmic diet plus administration of puerarin (300 mg/kg/day, p.o.) for 4 weeks. Puerarin markedly attenuated the increased total cholesterol induced by hypercholesterolmic diet in both serum and liver. It caused a significant reduction in the atherogenic index. Expression of mRNA for hepatic 7alpha-hydroxylase (CYP7A1) was significantly enhanced but not for those of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and lanosterol 14alpha-demethylase (CYP51). To further explore the atheroscleroprotective potential of puerarin, acetylcholine induced endothelium-dependent vasorelaxation and endothelial nitric oxide synthase (eNOS) expression on isolated thoracic aortas were analyzed. Animals administered with puerarin suppressed the hypercholesterolemic diet induced impairment of eNOS expression, whereas there was no significant difference in the endothelium-dependent vasorelaxation among various groups of animals. These data indicated that puerarin reduced the atherogenic properties of dietary cholesterol in rats. Its hypocholesterolemic function may be due to the promotion of cholesterol and bile acids excretion in liver. Whether puerarin targets directly on cholesterol homeostasis or both cholesterol homeostasis and endothelial function remains to be determined.
Assuntos
Aorta Torácica/efeitos dos fármacos , Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Isoflavonas/uso terapêutico , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatadores/uso terapêutico , Acetilcolina/farmacologia , Animais , Aorta Torácica/enzimologia , Colesterol 7-alfa-Hidroxilase/biossíntese , Colesterol 7-alfa-Hidroxilase/genética , Colesterol na Dieta/administração & dosagem , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Hidroximetilglutaril-CoA Redutases/biossíntese , Hidroximetilglutaril-CoA Redutases/genética , Hipercolesterolemia/sangue , Hipercolesterolemia/induzido quimicamente , Masculino , Medicina Tradicional Chinesa , Óxido Nítrico Sintase Tipo III/genética , Oxirredutases/biossíntese , Oxirredutases/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Esterol 14-DesmetilaseRESUMO
Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. Based on the core structure of cantharidin, we have chemically synthesized two cantharidin analogues (compounds 2 and 3). The cytotoxic activity of these analogues was demonstrated on the Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer, A549 non-small cell lung carcinoma and KG1a acute myelogenous leukaemia (AML) cell lines by monitoring the intracellular adenosine triphosphate level. Morphological changes in these cancer cell lines, including cell shrinkage and loss of adherent potential, were readily observed. By making use of the KG1a AML cells as a test model, we further found that mitochondrial membrane potential depolarization and reduction of intracellular bcl-2 anti-apoptotic protein level were involved. These resulted in the activation of caspase 3 protease activity and oligonucleosomal length DNA fragment formation as detected by both time resolved fluorescence technology-based caspase activity assay and TdT-mediated dUTP nick end-labelling assay.
Assuntos
Apoptose/fisiologia , Cantaridina , Linhagem Celular Tumoral/efeitos dos fármacos , Inibidores Enzimáticos , Trifosfato de Adenosina/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Cantaridina/síntese química , Cantaridina/química , Cantaridina/farmacologia , Caspase 3 , Caspases/metabolismo , Forma Celular , Células Cultivadas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Marcação In Situ das Extremidades Cortadas , Mitocôndrias/metabolismo , Estrutura MolecularRESUMO
Cantharidin isolated from Mylabris caraganae and other insects is used traditionally as an anti-cancer drug. However, its toxicity on the renal system and suppression effect on bone marrow limits its clinical usage. Recently, we have synthesized two cantharidin analogues, CAN 029 (compound 2) and CAN 030 (compound 3). Although both showed an apoptotic induction ability on cancer cells, they were still relatively toxic towards non-malignant haematological disordered bone marrow. Based on the principle structure of cantharidin, we have further chemically synthesized another analogue, CAN 032. The cytotoxic activity of this analogue was screened on both Hep3B hepatocellular carcinoma and SK-Hep-1 liver adenocarcinoma cell lines by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay. Morphological changes of hepatoma cell lines were recorded under an inverted microscope. The possible tolerance of these analogues was further investigated using non-malignant haematological bone marrow primary culture. CAN 032 showed a significant cytotoxic response on both hepatoma cell lines in which the potencies were comparable to that of cantharidin. Further screening on the bone marrow tolerance revealed that compound CAN 032 showed a relatively less toxic effect. Phase contrast microscopy demonstrated that cell shrinkage, rounding, loss of adherent property and loss of colony-formation ability were induced. The dose-dependence of the response of CAN 032 on Hep3B was further assayed by DNA fragmentation gel electrophoresis. The G1 peak of Hep3B cells was reduced. Chemically synthesized CAN 032 may provide an improved therapeutic advantage over traditional cantharidin.