RESUMEN

Two unprecedented quinone compounds Rubiaxylm A (1) and Rubiaxylm B (2), along with fifteen known anthraquinones (3-17) were isolated and characterized from the roots of Rubia tibetica in Tibetan medicine. Their structures were identified through comprehensive analyses of 1D/2D NMR as well as HR-ESIMS data. Furthermore, all separated compounds were evaluated for their cytotoxic activity on A549, Caco-2, MDA-MB-231 and Skov-3 cell lines. In particular, compound 2 effectively inhibited MDA-MB-231 cells with an IC50 value of 8.15 ± 0.20 µM. Subsequently, the anti-tumor mechanism of 2 was investigated by flow cytometry, JC-1 staining, cell scratching and cell colony. These results indicated that compound 2 could inhibit the proliferation of MDA-MB-231 cells by arresting cells in the G1 phase.

Asunto(s)

Antineoplásicos Fitogénicos , Medicina Tradicional Tibetana , Fitoquímicos , Raíces de Plantas , Rubia , Humanos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Línea Celular Tumoral , Rubia/química , Raíces de Plantas/química , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Antraquinonas/farmacología , Antraquinonas/aislamiento & purificación , Antraquinonas/química , Tibet , Quinonas/farmacología , Quinonas/aislamiento & purificación , Quinonas/química

RESUMEN

Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.

Asunto(s)

Leishmania braziliensis , Leishmaniasis Cutánea , Neoplasias , Humanos , Ratones , Animales , Monocitos

RESUMEN

Two unprecedented oleane-type triterpenes (5-6) were isolated from the roots of Astilbe grandis Stapf ex Wils, along with four known triterpenes (1-4), all of which were separated from this plant for the first time. The structures of these compounds were elucidated on the basis of spectroscopic analyses especially analysis of 2D NMR data, and the absolute configurations of 5 and 6 were determined by comparison of experimental and calculated ECD data. The structure of 5 was further confirmed by single crystal X-ray diffraction analysis. Compounds 1-6 were evaluated for their in vitro anti-tumor activities on A549, Caco-2, H460 and Skov-3 cells lines. All of the compounds exhibited obvious anti-Caco-2 activity with IC50 values ranging from 1.86 to 4.94 µM, among of them compound 6 also had the apparent effect on A549 cells. In addition, compounds 1, 4 and 5 were evaluated relatively strong inhibitory activity against H460 cells' growth with IC50 values of 5.13 µM, 5.65 µM and 8.85 µM respectively.

Asunto(s)

Triterpenos , Humanos , Triterpenos/farmacología , Triterpenos/química , Estructura Molecular , Línea Celular , Células A549

RESUMEN

Flaxseed consumption (Linum usitatissimum L.) has increased due to its potential health benefits, such as protection against inflammation, diabetes, cancer, and cardiovascular diseases. However, flaxseeds also contains various anti-nutritive and toxic compounds such as cyanogenic glycosides, and phytic acids etc. In this case, the long-term consumption of flaxseed may pose health risks due to these non-nutritional substances, which may be life threatening if consumed in high doses, although if appropriately utilized these may prevent/treat various diseases by preventing/inhibiting and or reversing the toxicity induced by other compounds. Therefore, it is necessary to remove or suppress the harmful and anti-nutritive effects of flaxseeds before these are utilized for large-scale as food for human consumption. Interestingly, the toxic compounds of flaxseed also undergoes biochemical detoxification in the body, transforming into less toxic or inactive forms like α-ketoglutarate cyanohydrin etc. However, such detoxification is also a challenge for the development, scalability, and real-time quantification of these bioactive substances. This review focuses on the health affecting composition of flaxseed, along with health benefits and potential toxicity of its components, detoxification methods and mechanisms with evidence supported by animal and human studies.

Asunto(s)

Lino , Lino/química

RESUMEN

Six undescribed stilbene derivatives Reflexanbene DH (1-4, 6) and Reflexanbene J (5), as well as one known stilbene 3,5-dimethoxystilbene (7), were isolated from the dried roots of Lindera reflexa Hemsl. Their structures and absolute configurations were elucidated using spectroscopy and electronic circular dichroism (ECD) analysis. In cytotoxic assays, moderately inhibitory activities of Reflexanbene F (3) against MGC80-3 and A549 cell lines were observed, with IC50 values of 15.42 and 5.09 µM, respectively. The IC50 value of Reflexanbene E (2) on A549 cell lines was 19.78 µM. The isolated compounds were also tested for their inhibitory effect against LPS-induced NO and IL-6 production in RAW 264.7 cells. In particular, Reflexanbene J (5) and Reflexanbene H (6) showed significant inhibition of NO production in LPS-stimulated macrophage RAW 264.7 cells at the concentration of 20 µM. Furthermore, the expression of IL-6 protein in the LPS-induced RAW 264.7 cells can also be significantly inhibited by different concentrations (5, 10 and 20 µM, p < 0.05 or p < 0.01) of compounds 1-7.

Asunto(s)

Antiinflamatorios , Antineoplásicos , Lindera , Estilbenos , Humanos , Antiinflamatorios/farmacología , Interleucina-6 , Lindera/química , Lipopolisacáridos , Estructura Molecular , Estilbenos/farmacología , Estilbenos/química , Células A549 , Células RAW 264.7 , Animales , Ratones , Antineoplásicos/farmacología

RESUMEN

The apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G) converts cytosine to uracil in DNA/RNA. Its role in resisting viral invasion has been well documented. However, its expression pattern and potential function in AML remain unclear. In this study, we carried out a bioinformatics analysis and revealed that the expression of APOBEC3G was significantly upregulated in AML, and high expression of APOBEC3G was significantly associated with short overall survival (OS). APOBEC3G expression was especially increased in non-M3AML, and correlated with the unfavorable cytogenetic risks. Additionally, Cox regression analyses indicated APOBEC3G is a hazard factor that cannot be ignored for OS of AML patients. In molecular docking simulations, the natural product crotonoside was found to interact well with APOBEC3G. The expression of APOBEC3G is the highest in KG-1 cells, and the treatment with crotonoside can reduce the expression of APOBEC3G. Crotonoside can inhibit the viability of different AML cells in vitro, arrest KG-1 and MV-4-11 cells in the S phase of the cell cycle and affect the expression of cycle-related proteins, and induce cell apoptosis. Therefore, APOBEC3G could be a potential drug target of crotonoside, and crotonoside can be considered as a lead compound for APOBEC3G inhibition in non-M3 AML.

Asunto(s)

Productos Biológicos , VIH-1 , Leucemia Mieloide Aguda , Desaminasas APOBEC-1 , Desaminasa APOBEC-3G/genética , Adenosina , Biomarcadores , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Citosina , Guanosina , VIH-1/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Simulación del Acoplamiento Molecular , Pronóstico , ARN , Uracilo

RESUMEN

Natural products (NPs) are always the important sources in the field of drug discovery, among which spirolactone-type and enmein-type compounds exhibit a wide range of biological activities, especially anti-tumor activity. Based on previous studies, the spirolactone-type and enmein-type compounds could be derived from natural oridonin (1) by several chemical reactions. Herein, a series of novel spirolactone-type and enmein-type derivatives with different aryl allyl ester substitutions at their C-14 hydroxyl group were designed and synthesized. The anti-tumor activity results showed that most of the compounds exhibited better anti-proliferative activities than parent compound oridonin, and the most potent compound had an IC50 value of 0.40 µM in K562 cells. Further mechanistic studies revealed that the optimal compound could arrest K562 cells at G2/M phase by inhibiting cdc-2, cdc-25c and cyclin B1 expression. In addition, the optimal compound induced apoptosis in K562 cells through increasing ROS production and depolarizing mitochondrial membrane potential. Collectively, these valuable results suggested that the most potent compound could be an anti-tumor agent candidate and is worthy of further investigation.

Asunto(s)

Antineoplásicos , Productos Biológicos , Diterpenos de Tipo Kaurano , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Productos Biológicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Ciclina B1 , Diterpenos , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Ésteres/farmacología , Humanos , Especies Reactivas de Oxígeno , Espironolactona/química , Espironolactona/farmacología , Relación Estructura-Actividad

RESUMEN

Thirteen undescribed diterpenoid quinones were isolated from the dried roots of Salvia miltiorrhiza. Their structures were determined by extensive analysis, including NMR, HRESIMS, and IR. Their absolute configurations were determined by X-ray diffraction, calculated and experimental circular dichroism spectroscopy, and optical rotation. In the evaluation of bioactivities, salviadionether obviously inhibited the proliferation of HCT-116 cells. R-(+)-salmiltiorin E and R-(+)-grandifolia D both showed inhibitory activities on a variety of tumor cells. Salvianone ester A showed strong cytotoxicity to tumor-repopulating cells (TRCs) with an IC50 value of 2.19 µM.

Asunto(s)

Diterpenos , Salvia miltiorrhiza , Salvia , Diterpenos/farmacología , Estructura Molecular , Raíces de Plantas , Quinonas/farmacología , Rizoma

RESUMEN

Drug delivery systems have good biocompatibiliy and low side effects for cancer treatment, but overcoming high efficiency of drug-loading and the drug-targeting controlled release still remains challenging. In this work, supramolecular vesicles, with pH-triggering effect, have been successfully constructed for drug delivery, which are fabricated by the complexation between a cationic pillar[5]arene (DAWP5) and a sodium dodecyl sulfonate (SDS) in aqueous solution. Drug-loading and releasing results demonstrated that anticancer drug doxorubicin (DOX) could be loaded efficiently by such cationic vesicles in neutral condition, and the drug release could be controlled in the simulated weak acid environment of tumor cells. Moreover, the vesicles had low cytotoxicity to normal human cell (L02), while the DOX-loaded vesicles could significantly enhance the cytotoxicity of free DOX for normal cell L02 and four tested tumor cells (Hela, HepG2, MGC-803 and T24). Especially for HepG2, after 24 h incubation time, IC50 of DOX-loaded vesicles was only 0.79 µM, about 23% of that of DOX (3.43 µM). These results suggested that such novel vesicles have promising potential to construct nano-drug delivery systems for various biomedical applications.

RESUMEN

We describe the use of natural product combretastatin A4 (CA4) as a versatile new payload for the construction of antibody-drug conjugates (ADCs). Cetuximab conjugates consisting of CA4 derivatives were site-specially prepared by disulfide re-bridging approach using cleavable and non-cleavable linkers. These ADCs retained antigen binding and internalization efficiency and exhibited high potencies against cancer cell lines in vitro. The conjugates also demonstrated significant antitumor activities in EGFR-positive xenograft models without observed toxicities. CA4 appears to be a viable payload option for ADCs research and development.

Asunto(s)

Cetuximab/química , Inmunoconjugados/química , Estilbenos/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Disulfuros , Diseño de Fármacos , Humanos , Inmunoconjugados/uso terapéutico , Masculino , Ratones , Ratones Endogámicos NOD , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Trasplante Heterólogo

RESUMEN

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.

Asunto(s)

Antineoplásicos/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Pirimidinas/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Unión Proteica , Conformación Proteica , Pirimidinas/farmacología , Transducción de Señal , Relación Estructura-Actividad

RESUMEN

Hot water extraction and chromatographic purification methods were used to extract and purify two polysaccharides (RAPS-1 and RAPS-2) from the roots of alfalfa. Subsequently, RAPS-2 was modified using the HNO3/Na2SeO3 method to obtain Se-RAPS-2. The structural features, antioxidant and in vitro anti-tumor activities of the three polysaccharides were evaluated. The structural analysis revealed that RAPS-1 (Mw = 10.0 kDa) was composed of rhamnose, xylose, arabinose, galacturonic acid, mannose and glucose, whereas RAPS-2 (Mw = 15.8 kDa) consisted of rhamnose, xylose, galacturonic acid, mannose, glucose and galactose. RAPS-1 contained 1 â†’ 2, 1 â†’ 4, 1 â†’ 3, and 1 â†’ 6 or 1 â†’ glycosidic bonds; however, while RAPS-2 lacked 1 â†’ 4 glycosidic linkages. The molecular weight of Se-RAPS-2 was 11.0 kDa less than that of RAPS-2. The results of activities demonstrated that Se-RAPS-2 displayed superior antioxidant activity and inhibitory effect in HepG2 cells than RAPS-1 and RAPS-2.

Asunto(s)

Antioxidantes/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Medicago sativa/química , Polisacáridos/farmacología , Antineoplásicos/química , Antioxidantes/química , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Células Hep G2 , Humanos , Raíces de Plantas/química , Polisacáridos/química , Selenio/química

RESUMEN

EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC50 values ranging from 1.0 to 1.7 µM, selectivity index (SI, as a logarithm of a ratio of IC50 value for normal and cancer cells) were all above 1.1, while the SI of EF24 and F35 were less than 0.8. Consistent with selectivity in vitro, 5B was observed to show lower toxicity in acute toxicity experiment than EF24 and F35 respectively. Further, 5B was found to exert anti-tumor effects through ROS-mediated activation of JNK pathway and inhibition of NF-κB pathway. 5B could significantly enhance the sensitivity of A549 cells to cisplatin or 5-Fu. These findings suggested that 5B was an effective and less toxic MCAC and provided a promising candidate for anti-tumor drugs.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Células A549 , Antineoplásicos/síntesis química , Curcumina/síntesis química , Diseño de Fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.

Asunto(s)

Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Semivida , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Relación Estructura-Actividad , Trasplante Heterólogo

RESUMEN

The antimicrobial activity and cytotoxicity in vitro of the fermentation broth of 10 endophytic strains isolated from Lycium barbarum were determined to screen high activity endophytic strains. Sequences analysis of ITS and 16S rDNA was used for molecular identification of the strains. The results showed that 5 endophytic fungi had no inhibitory activity against the tested pathogens. Endophytic actinomycete strain AL6 had a certain inhibitory effect on 3 kinds of pathogenic fungi, and strain AL5 only had strong inhibitory activity against Staphylococcus aureus. However, the anti-tumor activity of endophytic fungi was significantly higher than that of actinomycetes. Four endophytic fungi strains exhibited the growth inhibition rate of above 50% against at least one of the tested tumor cells when the concentration of fermentation broth was 0.2 g•L⁻¹. Sequences analysis showed that 5 endophytic fungi strains belonged to genus Aspergillus, Penicillium and Emericella, and the 5 endophytic actinomycetes strains belonged to genus Aspergillus, Penicillium and Emericella. Aspergillus strain FL1 had stronger inhibitory activity against A549 and HeLa cells, and the IC50 values were 0.022，0.028 g•L⁻¹, respectively, which was worthy of further study.

Asunto(s)

Antiinfecciosos/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Hongos/química , Lycium/microbiología , Células A549 , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Endófitos/química , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos

RESUMEN

(20R)-25-Methoxyl-dammarane-3ß,12ß,20-triol (25-OCH3-PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH3-PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH3-PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH3-PPD and its derivatives was tested and the results showed that the solubility of 25-OCH3-PPD sulfamic acid and diacid derivatives were better than that of 25-OCH3-PPD in water, which may provide valuable data for the research and development of new anti-tumor agents.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Agua/química , Línea Celular Tumoral , Ginsenósidos/química , Células HCT116 , Humanos , Células MCF-7 , Sapogeninas/química , Solubilidad , Ácidos Sulfónicos/química , Triterpenos/química , Damaranos

RESUMEN

BACKGROUND: DNA hypermethylation is a key epigenetic mechanism for the silencing of many genes in cancer. Hinokitiol, a tropolone-related natural compound, is known to induce apoptosis and cell cycle arrest and has anti-inflammatory and anti-tumor activities. However, the relationship between hinokitiol and DNA methylation is not clear. The aim of our study was to explore whether hinokitiol has an inhibitory ability on the DNA methylation in colon cancer cells. RESULTS: MTT data showed that hinokitiol had higher sensitivity in colon cancer cells, HCT-116 and SW480, than in normal colon cells, CCD18Co. Hinokitiol reduced DNA methyltransferase 1 (DNMT1) and ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression in HCT-116 cells. In addition, the expression of ten-eleven translocation protein 1 (TET1), a known DNA demethylation initiator, was increased by hinokitiol treatment. ELISA and FACS data showed that hinokitiol increased the 5-hydroxymethylcytosine (5hmC) level in the both colon cancer cells, but 5-methylcytosine (5mC) level was not changed. Furthermore, hinokitiol significantly restored mRNA expression of O6-methylguanine DNA methyltransferase (MGMT), carbohydrate sulfotransferase 10 (CHST10), and B-cell translocation gene 4 (BTG4) concomitant with reduction of methylation status in HCT-116 cells. CONCLUSIONS: These results indicate that hinokitiol may exert DNA demethylation by inhibiting the expression of DNMT1 and UHRF1 in colon cancer cells.

Asunto(s)

Proteínas Potenciadoras de Unión a CCAAT/antagonistas & inhibidores , Neoplasias del Colon/genética , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Metilación de ADN/efectos de los fármacos , Monoterpenos/farmacología , Tropolona/análogos & derivados , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Oxigenasas de Función Mixta/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Tiempo , Tropolona/farmacología , Ubiquitina-Proteína Ligasas

RESUMEN

The antimicrobial activity and cytotoxicity in vitro of the fermentation broth of 10 endophytic strains isolated from Lycium barbarum were determined to screen high activity endophytic strains. Sequences analysis of ITS and 16S rDNA was used for molecular identification of the strains. The results showed that 5 endophytic fungi had no inhibitory activity against the tested pathogens. Endophytic actinomycete strain AL6 had a certain inhibitory effect on 3 kinds of pathogenic fungi, and strain AL5 only had strong inhibitory activity against Staphylococcus aureus. However, the anti-tumor activity of endophytic fungi was significantly higher than that of actinomycetes. Four endophytic fungi strains exhibited the growth inhibition rate of above 50% against at least one of the tested tumor cells when the concentration of fermentation broth was 0.2 g•L⁻¹. Sequences analysis showed that 5 endophytic fungi strains belonged to genus Aspergillus, Penicillium and Emericella, and the 5 endophytic actinomycetes strains belonged to genus Aspergillus, Penicillium and Emericella. Aspergillus strain FL1 had stronger inhibitory activity against A549 and HeLa cells, and the IC₅₀ values were 0.022，0.028 g•L⁻¹, respectively, which was worthy of further study.

RESUMEN

HL-40, N-(4-(1-(4-chlorine indazole)) phenyl)-N-(4-chloro-3-three fluorine methyl phenyl) urea, is a novel diarylurea derivative. In this study, we investigated the kinases activities and binding constants, pharmacokinetics of HL-40, and then evaluated its anticancer efficacy by both in vitro and in vivo methods. Enzyme activities assays in vitro were employed to identify eight candidate kinase targets. The competition binding assays against eight candidate kinases suggested that HL-40 showed strong affinity to c-Kit, PDGFRß and FLT3. The pharmacokinetic studies in Wistar rats showed that HL-40 could maintain high compound concentration and long residence time in the blood circulation. HL-40 possessed strong inhibition activities against 12 human cancer cells. Meanwhile, HL-40 effectively delayed the growth of cancer xenografts without significant toxicity to mice. Based on these in vitro and in vivo results, we suggested that HL-40 might be developed as a potential multi-kinases inhibitor for cancer treatment.

Asunto(s)

Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Indazoles/farmacología , Indazoles/farmacocinética , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Urea/farmacología , Urea/farmacocinética , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pruebas de Enzimas , Humanos , Indazoles/administración & dosificación , Indazoles/química , Concentración 50 Inhibidora , Masculino , Ratones , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/química , Ratas Wistar , Urea/administración & dosificación , Urea/química , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Ardipusilloside I (ADS-I) is a natural compound that can be isolated from the Chinese medicinal herb Ardisiapusilla A.DC, and has been reported to inhibit the growth of glioblastoma cells in cultures. This study was designed to test its efficacy by the delivery using biodegradable implants against glioblastoma in vivo. ADS-I was incorporated into polymer microspheres, which were prepared by a mixture of poly (D, L-lactic acid) and poly (D, L-lactic-co-glycolic acid) polymers and then fabricated into wafers. The anti-glioma activities of ADS-I-loaded wafers were examined by methylthiazol tetrazolium (MTT) assay in cultured rat C6 glioma cells, and by magnetic resonance imaging (MRI) and survival monitoring in C6 glioma-bearing rats. Here, we showed that ADS-I-loaded wafers sustained ADS-I release in vitro for 36 days in Higuchi model of kinetics, and had the same cytotoxic activity as ADS-I in the solution against the growth of C6 glioma cells in cultures. In C6 glioma-bearing rats, ADS-I wafer implants inhibited tumor growth in a dose-dependent matter, and were more effective than the same dosage of ADS-I in the solution. The tumor suppression efficacies of ADS-I wafer implants were positively correlated with an increase in tumor cell apoptosis and prolonged animal survival, and were associated with a decrease in vascular endothelial growth factor, C-reactive protein, tumor necrosis factor-α and interleukin-6, and an increase in interleukin-2 expression. In conclusion, this study demonstrates significant efficacy of local delivery of ADS-I using polymer implants against glioma tumor growth in vivo, suggesting the potential of ADS-I-loaded wafers for glioma treatment.