RESUMEN
Synthesis and biological activity of two series of modified side chain methotrexate (MTX) derivatives are presented, one with a ferrocenyl moiety inserted between the pteroyl and glutamate portions of the molecule and the other with glutamate substituted for short chain amino acids. Ferrocenyl derivatives of MTX turned out to be rather moderate inhibitors of dihydrofolate reductase (DHFR) although molecular modeling suggested more effective interactions between these compounds and the target enzyme. More interestingly, ferrocene-decorated MTX derivatives were able to impede the proliferation of four murine and human cell lines as well as their methotrexate-resistant counterparts, overcoming the multidrug resistance (MDR) barrier. They were also able to directly interact with Abcc1, an MDR protein. Of the amino acid pteroyl conjugates, the γ-aminobutyric acid derivative was an efficient inhibitor of DHFR but had no effect on cell proliferation in the concentration range studied while a taurine conjugate was a poor DHFR inhibitor but able to affect cell viability. We postulate that modification of the methotrexate side chain may be an efficient strategy to overcome efflux-dependent methotrexate resistance.
RESUMEN
Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR phenomenon. The selection regimen allowed for overexpression of ABCG2 and ABCB1 both at the RNA and protein level, which was further confirmed by functional assays. Oncostatin M supplementation resulted in partial reversal of MDR phenotype by decreasing overexpression of ABCG2 demonstrating for the first time the ability of this cytokine for selective down-regulation of one of MDR proteins.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Resistencia a Antineoplásicos , Mitoxantrona , Proteínas de Neoplasias , Oncostatina M , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Mitoxantrona/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Oncostatina M/metabolismo , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genéticaRESUMEN
Kinesin spindle protein (KSP) inhibitors are one of the most promising anticancer agents developed in recent years. Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium. Conjugation of 7-chloroquinazolin-4(3H)-one with the pyridine-2-ylmethylimine group and the organometallic moiety resulted in up to a 36-fold increased cytotoxicity with IC50 values in the micromolar and nanomolar range also toward drug-resistant cells. All studied conjugates increased the percentage of cells in the G2/M phase, simultaneously decreasing the number of cells in the G1/G0 phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action.
RESUMEN
Antimitotic agents are among the most important drugs used in anticancer therapy. Kinesin spindle protein (KSP) was proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its (S)-enantiomer. Conjugation of the organometallic moiety with ispinesib and its (S)-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC50 values in the nanomolar range. The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation.
Asunto(s)
Antimitóticos , Antineoplásicos , Compuestos Organometálicos , Antimitóticos/farmacología , Especies Reactivas de Oxígeno , Quinazolinas , Benzamidas/metabolismo , Benzamidas/farmacología , Compuestos Organometálicos/farmacologíaRESUMEN
With the aim to combine more than one biologically-active component in a single molecule, derivatives of ispinesib and its (S) analogue were prepared that featured ferrocenyl moieties or bulky organic substituents. Inspired by the strong kinesin spindle protein (KSP) inhibitory activity of ispinesib, the compounds were investigated for their antiproliferative activity. Among these compounds, several derivatives demonstrated significantly higher antiproliferative activity than ispinesib with nanomolar IC50 values against cell lines. Further evaluation indicated that the antiproliferative activity is not directly correlated with their KSP inhibitory activity while docking suggested that several of the derivatives may bind in a manner similar to ispinesib. In order to investigate the mode of action further, cell cycle analysis and reactive oxygen species formation were investigated. The improved antiproliferative activity of the most active compounds may be assigned to synergic effects of various factors such as KSP inhibitory activity due to the ispinesib core and ability to generate ROS and induce mitotic arrest.
Asunto(s)
Antineoplásicos , Cinesinas , Metalocenos , Línea Celular , Antineoplásicos/farmacologíaRESUMEN
Importance: Intranasal corticosteroids (INCs) remain the first-line treatment of chronic rhinosinusitis (CRS) in both adults and children, despite the lack of evidence regarding their efficacy in the pediatric population. Similarly, their effect on the sinonasal microbiome has not been well documented. Objective: To assess the clinical, immunological, and microbiological effects of 12 weeks of an INC in young children with CRS. Design, Setting, and Participants: This open-label randomized clinical trial was performed in a pediatric allergy outpatient clinic in 2017 and 2018. Children aged 4 to 8 years with CRS diagnosed by a specialist were included. Data were analyzed from January 2022 to June 2022. Interventions: Patients were randomized to receive intranasal mometasone in an atomizer for 12 weeks (1 application per nostril, once per day) and supplemental 3-mL sodium chloride (NaCl), 0.9%, solution in a nasal nebulizer once a day for 12 weeks (INC group) or 3-mL NaCl, 0.9%, solution in a nasal nebulizer once a day for 12 weeks (control group). Main Outcomes and Measures: Measures taken both before and after treatment included the Sinus and Nasal Quality of Life Survey (SN-5), a nasopharynx swab for microbiome analysis by next-generation sequencing methods, and nasal mucosa sampling for occurrence of innate lymphoid cells (ILCs). Results: Of the 66 children enrolled, 63 completed the study. The mean (SD) age of the cohort was 6.1 (1.3) years; 38 participants (60.3%) were male and 25 (39.7%) were female. The clinical improvement reflected by reduction in SN-5 score was significantly higher in the INC group compared with the control group (INC group score before and after treatment, 3.6 and 3.1, respectively; control group score before and after treatment, 3.4 and 3.8, respectively; mean between-group difference, -0.58; 95% CI, -1.31 to -0.19; P = .009). The INC group had a greater increase in nasopharyngeal microbiome richness and larger decrease in nasal ILC3 abundance compared with the control group. A significant interaction was observed between change in microbiome richness and the INC intervention on the prediction of significant clinical improvement (odds ratio, 1.09; 95% CI, 1.01-1.19; P = .03). Conclusions and Relevance: This randomized clinical trial demonstrated that treatment with an INC improved the quality of life of children with CRS and had a significant effect on increasing sinonasal biodiversity. Although further investigation is needed of the long-term efficacy and safety of INCs, these data may reinforce the recommendation of using INCs as a first-line treatment of CRS in children. Trial Registration: ClinicalTrials.gov Identifier: NCT03011632.
Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Adulto , Niño , Masculino , Humanos , Femenino , Preescolar , Calidad de Vida , Cloruro de Sodio/uso terapéutico , Inmunidad Innata , Pólipos Nasales/tratamiento farmacológico , Rinitis/tratamiento farmacológico , Linfocitos , Corticoesteroides/uso terapéutico , Sinusitis/tratamiento farmacológico , Enfermedad Crónica , Resultado del TratamientoRESUMEN
The incorporation of the ferrocenyl moiety into a bioactive molecule may significantly alter the activity of the resulting conjugate. By applying this strategy, we designed ferrocenyl analogs of monastrol - the first low molecular weight kinesin spindle protein (KSP) inhibitor. The obtained compounds showed low micromolar antiproliferative activity towards a panel of sensitive and ABC-overexpressing cancer cells. Most cytotoxic compounds exhibited also higher KSP modulatory activity and ability for ROS generation compared to monastrol. The increased bioactivity of the studied compounds can be attributed to the presence of the ferrocenyl group.
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Antineoplásicos/farmacología , Compuestos Ferrosos/farmacología , Cinesinas/antagonistas & inhibidores , Pirimidinas/farmacología , Tionas/farmacología , Adenosina Trifosfatasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Two series of the ferrocenyl and ruthenocenyl analogues of etoposide bearing 1,2,3-triazolyl or aminoalkyl linker were synthesized and evaluated for their cytotoxic properties, influence on the cell cycle, ability to induce tubulin polymerization, and inhibition of topoisomerase II activity. We found that the replacement of the etoposide carbohydrate moiety with a metallocenyl group led to organometallic conjugates exhibiting differentiated antiproliferative activity. Biological studies demonstrated that two ferrocenylalkylamino conjugates were notably more active than etoposide, with submicromolar or low-micromolar IC50 values towards SW620, etoposide-resistant SW620E, and methotrexate-resistant SW620M cancer cell lines. Moreover, the simplest ferrocenylmethylamino conjugate exerted dual inhibitory action against tubulin polymerization and topoisomerase II activity while other studied compounds affected only topoisomerase II activity.
Asunto(s)
Antineoplásicos , Tubulina (Proteína) , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo II/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Etopósido/farmacología , Polimerizacion , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/farmacología , Tubulina (Proteína)/metabolismoRESUMEN
BACKGROUND: Innate immunity response to local dysbiosis seems to be one of the most important immunologic backgrounds of chronic rhinosinusitis (CRS) and concomitant asthma. We aimed to assess clinical determinants of upper-airway dysbiosis and its effect on nasal inflammatory profile and asthma risk in young children with CRS. METHODS: We recruited one hundred and thirty-three children, aged 4-8 years with doctor-diagnosed CRS with or without asthma. The following procedures were performed in all participants: face-to-face standardized Sinus and Nasal Quality of Life questionnaire, skin prick test, taste perception testing, nasopharynx swab, and sampling of the nasal mucosa. Upper-airway dysbiosis was defined separately by asthma-specific microbiome composition and reduced biodiversity. Multivariate methods were used to define the risk factors for asthma and upper-airway dysbiosis and their specific inflammatory profile of nasal mucosa. RESULTS: The asthma-specific upper-airway microbiome composition reflected by the decreased ratio of Patescibacteria/Actinobacteria independently of atopy increased the risk of asthma (OR:8.32; 95%CI: 2.93-23.6). This asthma-specific microbiome composition was associated with ≥ 7/week sweet consumption (OR:2.64; 95%C:1.11-6.28), reduced biodiversity (OR:3.83; 95%CI:1.65-8.87), the presence of Staphylococcus strains in the nasopharynx (OR:4.25; 95%CI:1.12-16.1), and lower expression of beta-defensin 2, IL-5, and IL-13 in the nasal mucosa. The reduced biodiversity was associated with frequent antibiotic use and with a higher nasal expression of IL-17 and T1R3 (sweet taste receptor). In asthmatic children, reduced sweet taste perception was observed. CONCLUSIONS: Specific upper-airway dysbiosis related to frequent sweet consumption, frequent antibiotic courses, and altered nasal immune function increases the risk of asthma in young children with CRS.
Asunto(s)
Asma , Pólipos Nasales , Rinitis , Sinusitis , Asma/epidemiología , Niño , Preescolar , Enfermedad Crónica , Disbiosis , Humanos , Calidad de Vida , Rinitis/epidemiología , Sinusitis/epidemiologíaRESUMEN
Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N,N-bidentate ligands (R)- and (S)-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure (R)- and (S)-forms of the ligand, depending on the organometallic moiety, either the SM,R or RM,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η6-p-cymene) compounds, whereas the RM,R or SM,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Complejos de Coordinación/farmacología , Cinesinas/antagonistas & inhibidores , Quinazolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antioxidantes/síntesis química , Antioxidantes/metabolismo , Antioxidantes/farmacología , Benzamidas/síntesis química , Benzamidas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cinesinas/metabolismo , Ligandos , Metales Pesados/química , Simulación del Acoplamiento Molecular , Unión Proteica , Quinazolinas/síntesis química , Quinazolinas/metabolismo , EstereoisomerismoRESUMEN
Our laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Alcaloides/farmacología , Antineoplásicos/farmacología , Hipoxantina/farmacología , Microtúbulos/efectos de los fármacos , Pirimidinas/farmacología , Pirroles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Alcaloides/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Hipoxantina/síntesis química , Hipoxantina/química , Células MCF-7 , Células de Riñón Canino Madin Darby/efectos de los fármacos , Microtúbulos/metabolismo , Estructura Molecular , Pirimidinas/química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Correction for 'Colchicine metallocenyl bioconjugates showing high antiproliferative activities against cancer cell lines' by Karolina Kowalczyk et al., Dalton Trans., 2017, 46, 17041-17052.
RESUMEN
A series of ferrocenyl and ruthenocenyl conjugates with colchicine bearing a 1,2,3-triazole moiety were synthesized and their anticancer properties were evaluated. We found that the most potent metallocenyl derivatives Rc4 and Rc5 are 6-7 times more cytotoxic toward HepG2 cells, while Fc4 and Fc5 are two times more cytotoxic toward HCT116 cells as colchicine. We also found that compounds Fc4, Fc5, Rc1 and Rc3-Rc5 are able to induce apoptosis, while compound Fc2 arrests mitosis.
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Antineoplásicos/química , Antineoplásicos/farmacología , Colchicina/química , Colchicina/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Compuestos Ferrosos/química , Células HCT116 , Humanos , Metalocenos/química , Mitosis/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , Estructura Cuaternaria de Proteína , Especies Reactivas de Oxígeno/metabolismo , Triazoles/química , Tubulina (Proteína)/químicaRESUMEN
Taxanes, including paclitaxel, are widely used in cancer therapy. In an attempt to overcome some of the disadvantages entailed with taxane chemotherapy, we devised the synthesis of ferrocenyl-functionalized paclitaxel derivatives and studied their biological properties. The cytotoxic activity was measured with a panel of human cancer cell lines of various tissue origin, including multidrug-resistant lines. A structure-activity study of paclitaxel ferrocenylation revealed the N-benzoyl-ferrocenyl-substituted derivative to be the most cytotoxic. In contrast, substitution of the 3'-phenyl group of paclitaxel with a ferrocenyl moiety led to less potent antiproliferative compounds. However, these agents were able to overcome multidrug resistance, as they were virtually unrecognized by ABCB1, a major cellular exporter of taxanes. Interestingly, the redox properties of these ferrocenyl derivatives appear to play a less important role in their mode of action, as there was no correlation between intracellular redox activity and cytotoxicity/cell-cycle distribution. The antiproliferative activity of ferrocenyl taxanes strongly depends on the substitution position, and good tubulin polymerization inducers, as confirmed by molecular docking, were usually more cytotoxic, whereas compounds with stronger pro-oxidative properties exhibited lower antiproliferative activity.
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Antineoplásicos/farmacología , Compuestos Ferrosos/farmacología , Paclitaxel/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Ferrosos/química , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Paclitaxel/síntesis química , Paclitaxel/química , Polimerizacion/efectos de los fármacos , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
Polyhedral oligomeric silsesquioxane (POSS), bearing eight 3-chloroammoniumpropyl substituents, was studied as a potential nanocarrier in co-delivery systems with doxorubicin (DOX). The toxicity of doxorubicin and POSS:DOX complexes at four different molar ratios (1:1; 1:2, 1:4, 1:8) towards microvascular endothelial cells (HMEC-1), breast cancer cells (MCF-7), and human cervical cancer endothelial cells (HeLa) was determined. The rate of penetration of the components into the cells, their cellular localization and the hydrodynamic diameter of the complexes was also determined. A cytotoxicity profile of POSS:DOX complexes indicated that the POSS:DOX system at the molar ratio of 1:8 was more effective than free DOX. Confocal images showed that DOX co-delivery with POSS allowed for more effective penetration of doxorubicin through the cell membrane. Taking all the results into account, it can be claimed that the polyhedral oligomeric silsesquioxane (T8-POSS) is a promising, complex nanocarrier for doxorubicin delivery.
RESUMEN
Three types, esters, amides and 1,2,3-triazoles, of ferrocenyl-podophyllotoxin conjugates were synthesised, and their anticancer activity was evaluated. We observed that the most potent ferrocenyl derivatives were esters. Esters 15, 16 and 17 acted in a similar way to podophyllotoxin, i.e. reduced the number of G1 phase cells and induced G2/M blockage, while esters 14 and 18 and amide 19 blocked cells in S phase in a similar manner to etoposide.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos Ferrosos/química , Metalocenos/química , Podofilotoxina/síntesis química , Podofilotoxina/farmacología , Amidas/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Química Sintética , Esterasas/metabolismo , Humanos , Modelos Moleculares , Conformación Molecular , Podofilotoxina/química , Podofilotoxina/metabolismo , Multimerización de Proteína/efectos de los fármacos , Estructura Cuaternaria de Proteína , Triazoles/química , Tubulina (Proteína)/químicaRESUMEN
Through the selection with five chemotherapeutics of diverse chemical structures and modes of action (cis-diamminedichloroplatinum, doxorubicin, etoposide, methotrexate and vincristine), four multidrug-resistant cell line panels were developed. Cancer cell lines of different species (human and murine) as well as tissue/organ (skin, colon) origin, characterized by low endogenous expression of multidrug resistance (MDR) proteins and high sensitivity to anticancer agents, were used as parental cell lines. A selection process resulted in the upregulation of several ABC transporters (ABCB1/Abcb1a, ABCC1/Abcc1 and ABCG2/Abcg2), which was confirmed by a number of molecular and cell biology methods. The MDR protein expression pattern seemed to be mainly dependent on the drug used for the selection and not on the species or tissue origin of the cell line. We postulate that such cell panels can be used as a research model to assess the role of MDR proteins in the pharmacokinetics of novel drugs or drug formulations.
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Subfamilia B de Transportador de Casetes de Unión a ATP/biosíntesis , Antineoplásicos/farmacocinética , Animales , Línea Celular Tumoral , Humanos , Melanoma Experimental/metabolismo , Ratones , Especificidad de la EspecieRESUMEN
BACKGROUND: An important issue in sublingual immunotherapy (SLIT) is how to improve efficacy. OBJECTIVE: To compare the clinical and immunologic efficacy of SLIT given alone and, to enhance clinical efficacy, given with probiotic or vitamin D supplementation. METHODS: One hundred children, ages 5-12 years, sensitive to grass pollen, with allergic rhinitis participated in a 5-month prospective, randomized, double-blind, placebo-controlled trial. Children received 5-grass SLIT 300 IR tablets with either vitamin D 1000 IU daily supplementation, probiotic, or placebo. The control group included children with allergy who did not qualify for immunotherapy. Primary end points included a symptom-medication score, lung function, and exhaled nitric oxide concentration. The secondary end point was the immunologic efficacy measured by the following: CD4(+)CD25(+)Foxp3(+) (forkhead box P3) cells, Toll-like receptor (TLR) 4, interleukin (IL) 1, IL-6, tumor necrosis factor, IL-10, and transforming growth factor ß-1 levels in cell culture supernatants. RESULTS: Reduction in the symptom-medication score and improvement in lung function as well as a significant increase in the percentage of CD4(+)CD25(+)Foxp3(+) in children who received SLIT in all the groups were observed compared with control group. In the SLIT-probiotic group, between-group analysis showed significantly higher CD4(+)CD25(+)Foxp3(+) induction compared with the SLIT group and higher reduction in the percentage of TLR-positive cell group compared with the SLIT-vitamin D group (Fig. 1). An increase in CD4(+)CD25(+)Foxp3(+) induction, reduction in TLR-positive cells recruitment and an increase in transforming growth factor ß-1 production were independently associated with a better clinical effect of SLIT in children. CONCLUSIONS: We demonstrated the clinical and immunologic effect of probiotic and vitamin D supplementation on SLIT. Probiotic supplementation showed better clinical and immunologic response in children with allergic rhinitis.
Asunto(s)
Alérgenos/inmunología , Suplementos Dietéticos , Lacticaseibacillus rhamnosus , Poaceae/efectos adversos , Probióticos , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Inmunoterapia Sublingual , Vitamina D/administración & dosificación , Alérgenos/administración & dosificación , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Polen/inmunología , Probióticos/administración & dosificación , Pronóstico , Pruebas de Función Respiratoria , Rinitis Alérgica Estacional/diagnóstico , Estaciones del Año , Inmunoterapia Sublingual/efectos adversos , Inmunoterapia Sublingual/métodos , Resultado del TratamientoRESUMEN
A series of ferrocenyl analogues and derivatives of paclitaxel and docetaxel were synthesised and assayed for their antiproliferative/cytotoxic effects, impact on the cell cycle distribution and ability to induce tubulin polymerisation. The replacement of the 3'-N-benzoyl group of paclitaxel with a ferrocenoyl moiety, in particular, led to formation of an analogue that was at least one order of magnitude more potent in terms of antiproliferative activity than the parent compound (IC50 values of 0.11 versus 1.11â µm, respectively), but still preserved the classical taxane mode of action, that is, microtubule stabilisation leading to mitotic arrest. Molecular docking studies revealed an unexpected binding pocket in the tubulin structure for the ferrocenoyl group introduced in the paclitaxel backbone.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Compuestos Organometálicos/química , Paclitaxel/química , Taxoides/química , Tubulina (Proteína)/química , Docetaxel , Humanos , Simulación del Acoplamiento Molecular , Paclitaxel/metabolismo , Taxoides/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
The tubulin-microtubule system is a common target of many anticancer drugs. However, the use of chemotherapeutics frequently leads to the development of a clinically relevant phenomenon of multidrug resistance (MDR). One of the basic mechanisms involved in MDR involves elevated expression and/or activity of several ATP-binding cassette superfamily members (ABC transporters) which are normally responsible for the efflux of xenobiotics or secondary metabolites outside the cell. Here we present the synthesis and biological characteristics of ferrocenyl analogues of plinabulin, i.e. one of the so-called "spindle poisons". We found that replacement of the phenyl group of plinabulin by the ferrocenyl moiety turns this compound into a potent inhibitor of ABCB1 and ABCG2, thus making it possible to overcome the multidrug resistance phenomenon. We also demonstrated that the alkyl group attached to the imidazole moiety of ferrocenyl analogues of plinabulin strongly affects their potency to inhibit tubulin polymerization.