RESUMEN
OBJECTIVE: To investigate the effects of pomegranate leaves extract(PLE)on proliferation,apoptosis and metastasis of prostate cancer cells. METHODS: The proliferation of TRAMP-C1,DU145,PC3 prostate cancer cells treated with different concentrations of PLE (final mass concentrations were 12.5,25,50,100, 200 µg/mL,respectively) for different time (24,48,72 h) was detected by MTT assay. Colony formation assay was performed to verify the long-term effects of PLE on the proliferation of DU145 and PC3 cells.After being treated with PLE for 48 h,Hoechst-33258 staining was used to observe the changes in the nucleus,the cell apoptotic rate was detected by flow cytometry,and wound-healing migration assay was perform to test the change of migration. RESULTS: In comparison with the control group,PLE in the range of 12.5-200 µg/mL had a certain inhibitory effect on the proliferation of TRAMP-C1,DU145 and PC3 cells ( P<0.05).In the range of 6.25-100 µg/mL,the number of colony formation of DU145 and PC3 was significantly reduced( P<0.01).After PLE treated for 48 h, the apoptotic features of nuclear fragmentation and the formation apoptotic body was observed in PC3. With the increase of concentration,the apoptotic rate increased gradually ( P<0.05),and the ability of cells to migrate to the scratch area was significantly weaker than the control group ( P<0.01). CONCLUSION: PLE has effect on proliferation,apoptosis and metastasis of prostate cancer cells.
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Apoptosis/efectos de los fármacos , Lythraceae/química , Metástasis de la Neoplasia/patología , Extractos Vegetales/farmacología , Neoplasias de la Próstata/patología , Línea Celular Tumoral , Proliferación Celular , Humanos , Masculino , Metástasis de la Neoplasia/tratamiento farmacológico , Hojas de la Planta/química , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl)isoxazol-3-yl)-N'-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl)urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60 mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML.
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Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Femenino , Semivida , Humanos , Inmunohistoquímica , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/toxicidad , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante Heterólogo , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
BACKGROUND: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. METHODS: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor. RESULTS: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4(+) and CD8(+) T-cells were significantly increased in tumor and spleens. CONCLUSION: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.
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Benzamidas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/inmunología , Células Mieloides/inmunología , Piperazinas/farmacología , Pirazoles/farmacología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Mamarias Experimentales/patología , Ratones , Células Mieloides/patología , Metástasis de la NeoplasiaRESUMEN
Heme oxygenase-1 [HO-1, also called heat shot protein 32 (HSP32)] can specifically metabolize heme to carbon monoxide, biliverdin, and ferrous iron and plays an important role in the processes of anti-inflammation, tissue protection, and antioxidative stress reaction. It has been reported that HO-1 can promote tumorigenesis and metastasis of many tumors. However, the detailed mechanisms of how HO-1 affects tumor progress are not clear. Here, we used ZnPPIX (a specific inhibitor of HO-1) to evaluate its potential effects on mouse breast cancer and tumor-associated macrophages (TAMs). We found out that mouse 4T1 breast cancer growth can be effectively suppressed through inhibition of HO-1 in vitro and in vivo. Moreover, in the 4T1 mouse model, when HO-1 was suppressed in TAMs, alternatively activated macrophages (M2 type) switched to classically activated macrophages (M1 type). In conclusion, 4T1 breast cancer growth was modulated by HO-1 expression. Furthermore, inhibition of HO-1 may induce tumor-associated immune response by activating TAMs' alternative proliferation. These data suggest that HO-1 may be an important target of breast cancer treatment.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Hemo-Oxigenasa 1/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Proteínas de la Membrana/antagonistas & inhibidores , Protoporfirinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Hemo-Oxigenasa 1/metabolismo , Activación de Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/patología , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Necrosis , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 µM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.
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Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Tiazinas/química , Tiazinas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/farmacocinética , Chlorocebus aethiops , Humanos , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/farmacocinética , Tuberculosis/tratamiento farmacológico , Células VeroRESUMEN
A series of new 3-amino-5-sulfanyl-1,2,4-triazole and 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives have been synthesized and their cytotoxicities were evaluated on a panel of human cancer cell lines (BxPC-3, H1975, SKOV-3, A875, HCT116, etc.). The best one (compound 5m) exhibited activities with IC50 values ranging from 0.04 to 23.6 µM against nine human cancer cell lines. Further biological evaluation indicated that DNA replication was blocked by treatment with compound 5m in HCT116 cells.
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Antineoplásicos/química , Antineoplásicos/toxicidad , Tiadiazoles/química , Tiadiazoles/toxicidad , Triazoles/química , Triazoles/toxicidad , Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Triazoles/síntesis químicaRESUMEN
A novel series of N-methylpicolinamide-4-thiol derivatives were synthesized and evaluated on human cancer cell lines. Among them, compound 6p displayed potent and broad-spectrum anti-proliferative activities in vitro on some human cancer cell lines, even better than sorafenib. The advanced kinase inhibitory assays showed that compound 6p could selectively inhibit Aurora-B kinase. The biological results were rationalized by the molecular docking study, which indicated the stable interactions of 6p with the Aurora-B kinase.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacología , Antineoplásicos/química , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/químicaRESUMEN
A series of novel benzothiazole-2-thiol derivatives were synthesized and their structures determined by 1H-NMR, 13C-NMR and HRMS (ESI). The effects of all compounds on a panel of different types of human cancer cell lines were investigated. Among them, pyridinyl-2-amine linked benzothiazole-2-thiol compounds 7d, 7e, 7f and 7i exhibited potent and broad-spectrum inhibitory activities. Compound 7e displayed the most potent anticancer activity on SKRB-3 (IC(50) = 1.2 nM), SW620 (IC(50) = 4.3 nM), A549 (IC(50) = 44 nM) and HepG2 (IC(50) = 48 nM) and was found to induce apoptosis in HepG2 cancer cells.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzotiazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
In the title compound, C(18)H(21)N(3)O(2)S·0.5H(2)O, the benzene ring makes dihedral angles of 88.59â (6) and 40.74â (8)° with the pyridine ring and the amide group, respectively. The water O atom lies on a twofold axis. In the crystal, the organic mol-ecules and the water mol-ecules are linked via O-Hâ¯O hydrogen bonds, while the organic mol-ecules are connected to each other via N-Hâ¯O hydrogen bonds, forming a three-dimensional network.
RESUMEN
The mol-ecule of the title compound, C(10)H(9)N(3)S, is almost planar, with a dihedral angle of 1.38â (4)° between the thio-phene and pyridine rings. In the crystal packing, mol-ecules are linked into layers parallel to the ab plane by inter-molecular N-Hâ¯N hydrogen bonds and by πâ¯π stacking inter-actions involving adjacent pyridine and thio-phene rings with a centroid-centroid distance of 3.537â (3)â Å.
RESUMEN
Since publication of this article, the authors have noticed that there were errors in Fig. 1b (the CT 26 cells colony formation images) and Fig. 7c (the vehicle group images). As a result of the misfiling of the data during preparation of figures, incorrect images were inadvertently inserted in these figures.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.
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DspI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, was proposed to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule in the pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study provided a structural basis for the dehydration reaction mechanism of DspI during CDA synthesis. Structural analysis reveals that Glu126, Glu146, Cys127, Cys131 and Cys154 are important for its enzymatic function. Moreover, we show that the deletion of dspI results in a remarkable decreased in the pyoverdine production, flagella-dependent swarming motility, and biofilm dispersion as well as attenuated virulence in P. aeruginosa PA14. This study thus unravels the mechanism of DspI in diffusible signal factor (DSF) CDA biosynthesis, providing vital information for developing inhibitors that interfere with DSF associated pathogenicity in P. aeruginosa.
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Proteínas Bacterianas/metabolismo , Biopelículas/crecimiento & desarrollo , Enoil-CoA Hidratasa/metabolismo , Ácidos Grasos Monoinsaturados/metabolismo , Regulación Enzimológica de la Expresión Génica , Pseudomonas aeruginosa/metabolismo , Percepción de Quorum , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Movimiento Celular , Difusión , Enoil-CoA Hidratasa/química , Enoil-CoA Hidratasa/genética , Fimbrias Bacterianas/fisiología , Flagelos/fisiología , Modelos Moleculares , Conformación Proteica , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/patogenicidad , Homología de Secuencia , Transducción de Señal , Relación Estructura-Actividad , VirulenciaRESUMEN
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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New chemotherapeutic compounds and regimens are needed to combat multidrug-resistant Mycobacterium tuberculosis. Here, we used a series of murine models to assess an antitubercular lead compound SKLB-TB1001. In the Mycobacterium bovis bacillus Calmette-Guérin and the acute M. tuberculosis H37Rv infection mouse models, SKLB-TB1001 significantly attenuated the mycobacterial load in lungs and spleens. The colony forming unit counts and histological examination of lungs from H37Rv infected mice revealed that the benzothiazinethione analogue SKLB-TB1001 as a higher dose level was as effective as isoniazid. Moreover, in a multidrug-resistant (MDR)-TB mouse model, SKLB-TB1001 showed significant activity in a dose-dependent manner and was more effective than streptomycin. These results suggested that SKLB-TB1001 could be an antitubercular drug candidate worth further investigation.
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Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tiadiazoles/farmacología , Animales , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Femenino , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Análisis de Supervivencia , Tiadiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/uso terapéutico , Resultado del Tratamiento , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis/patologíaRESUMEN
Colorectal carcinoma (CRC) is the one of the most common cancers with considerable metastatic potential, explaining the need for new drug candidates that inhibit tumor metastasis. The signal transducers and activators of the transcription 3 (Stat3) signaling pathway has an important role in CRC and has been validated as a promising anticancer target for CRC therapy. In the present study, we report our findings on nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3. Our studies showed that nifuroxazide decreased the viability of three CRC cell lines and induced apoptosis of cancer cells in a concentration-dependent manner. Moreover, western blot analysis demonstrated that the occurrence of its apoptosis was correlated with the activation of Bax and cleaved caspase-3, and decreased the expression of Bcl-2. In addition, nifuroxazide markedly impaired CRC cell migration and invasion by downregulating phosphorylated-Stat3Tyr705, and also impaired the expression of matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, our studies showed that nifuroxazide also significantly inhibited the tumor metastasis in lung and abdomen metastasis models of colon cancer. Meanwhile, nifuroxazide functionally reduced the proliferation index, induced tumor apoptosis and impaired metastasis. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cells in the blood, spleens and tumors, accompanied by the increased infiltration of CD8+ T cells in the tumors. Importantly, a marked decrease in the number of M2-type macrophages in tumor in the abdomen metastasis model was also observed. Taken together, our results indicated that nifuroxazide could effectively inhibit tumor metastasis by mediating Stat3 pathway and it might have a therapeutic potential for the treatment of CRC.
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Apoptosis/genética , Neoplasias Colorrectales/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Factor de Transcripción STAT3/genética , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidroxibenzoatos/administración & dosificación , Ratones , Metástasis de la Neoplasia/genética , Proteínas de Neoplasias/biosíntesis , Nitrofuranos/administración & dosificación , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-ß-D-ribose 2'-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.
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Oxidorreductasas de Alcohol/antagonistas & inhibidores , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/enzimología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Oxidorreductasas de Alcohol/metabolismo , Antituberculosos/química , Proteínas Bacterianas/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/enzimología , Tuberculosis Resistente a Múltiples Medicamentos/patologíaRESUMEN
λ-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of λ-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of λ-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, λ-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-α in tumor, most of which was secreted by infiltrating macrophages. Moreover, λ-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that λ-carrageenan was with a good safety profile. Thus, λ-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy.
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Adyuvantes Inmunológicos/farmacología , Antineoplásicos/farmacología , Carragenina/farmacología , Inmunidad/efectos de los fármacos , Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Animales , Antineoplásicos/administración & dosificación , Vacunas contra el Cáncer/inmunología , Carragenina/administración & dosificación , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inyecciones Intralesiones , Interleucina-17/metabolismo , Melanoma Experimental/patología , Ratones , Neoplasias/patología , Especificidad de Órganos , Ovalbúmina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The design, synthesis, and SAR studies of novel inhibitors of HCV NS4B based on the imidazo[2,1-b]thiazole scaffold were described. Optimization of potency with respect to genotype 1b resulted in the discovery of two potent leads 26f (EC50 = 16 nM) and 28g (EC50 = 31 nM). The resistance profile studies revealed that 26f and 28g targeted HCV NS4B, more precisely the second amphipathic α helix of NS4B (4BAH2). Cross-resistance between our 4BAH2 inhibitors and other direct-acting antiviral agents targeting NS3/4A, NS5A, and NS5B was not observed. For the first time, the synergism of a series of combinations based on 4BAH2 inhibitors was evaluated. The results demonstrated that our 4BAH2 inhibitor 26f was synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitor daclatasvir, and NS5B inhibitor sofosbuvir, and it could also reduce the dose of these drugs at almost all effect levels. Our study suggested that favorable effects could be achieved by combining 4BAH2 inhibitors such as 26f with these approved drugs and that new all-oral antiviral combinations based on 4BAH2 inhibitors were worth developing to supplement or even replace current treatment regimens for curing HCV infection.
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Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Tiazoles/química , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Línea Celular , Sinergismo Farmacológico , Genotipo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatitis C/virología , Humanos , Mutación , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
PURPOSE: The universal organic solvent dimethyl sulfoxide (DMSO) can be used as a differentiation inducer of many cancer cells and has been widely used as a solvent in laboratories. However, its effects on breast cancer cells are not well understood. The aim of this study is to investigate the effect and associated mechanisms of DMSO on mouse breast cancer. METHODS: We applied DMSO to observe the effect on tumors in a mouse breast cancer model. Tumor-associated macrophages (TAMs) were tested by flow cytometry. Ex vivo tumor microenvironment was imitated by 4T1 cultured cell conditioned medium. Enzyme-linked immunosorbent assays were performed to detect interleukin (IL)-10 and IL-12 expression in medium. To investigate the cytotoxicity of DMSO on TAMs, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed. RESULTS: We found that DMSO produced tumor retardation when injected into mouse peritoneal cavities in a certain concentration range (0.5-1.0 mg/g). Furthermore, as detected by flow cytometry, TAM subtypes were found to be transformed. We further imitated a tumor microenvironment in vitro by using 4T1 cultured cell conditioned medium. Similarly, by using low concentration DMSO (1.0%-2.0% v/v), TAMs were induced to polarize to the classically activated macrophage (M1-type) and inhibited from polarizing into the alternatively activated macrophage (M2-type) in the conditioned medium. IL-10 expression in tumors was reduced, while IL-12 was increased compared with the control. Furthermore, we reported that 2.0% (v/v) DMSO could lead to cytotoxicity in peritoneal macrophages after 48 hours in MTT assays. CONCLUSION: Our findings suggest that DMSO could exert antitumor effects in 4T1 cancer-bearing mice by reversing TAM orientation and polarization from M2- to M1-type TAMs. These data may provide novel insight into studying breast cancer immunotherapy.