RESUMEN
Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) α, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3-independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRα, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal-regulated kinase 1/2 and the alternative NF-κB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-κB activation as a potential novel mechanism of resistance toward TKIs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carbazoles/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Enfermedad de Hodgkin/tratamiento farmacológico , FN-kappa B/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Células de Reed-Sternberg/efectos de los fármacos , Apoptosis/efectos de los fármacos , Carbazoles/administración & dosificación , Línea Celular Tumoral , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Furanos , Enfermedad de Hodgkin/enzimología , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Niacinamida/administración & dosificación , Niacinamida/farmacología , Compuestos de Fenilurea/administración & dosificación , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Células de Reed-Sternberg/enzimología , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Transducción de Señal/efectos de los fármacos , SorafenibAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Neoplasias Orbitales/tratamiento farmacológico , Quinazolinas/uso terapéutico , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cetuximab , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Quinazolinas/farmacologíaRESUMEN
Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma-secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (n = 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.
Asunto(s)
Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Proteínas Protozoarias/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Toxoplasma/efectos de los fármacos , Toxoplasmosis Animal/tratamiento farmacológico , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/parasitología , Genes Reporteros , Ensayos Analíticos de Alto Rendimiento , Interacciones Huésped-Parásitos , Humanos , Concentración 50 Inhibidora , Luciferasas , Ratones , Ratones Endogámicos BALB C , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Protozoarias/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Especificidad de la Especie , Relación Estructura-Actividad , Tasa de Supervivencia , Toxoplasma/crecimiento & desarrollo , Toxoplasmosis/tratamiento farmacológico , Toxoplasmosis/parasitología , Toxoplasmosis Animal/mortalidad , Toxoplasmosis Animal/parasitologíaRESUMEN
The antioxidant properties of α-tocopherol have been proposed to play a beneficial chemopreventive role against cancer. However, emerging data also indicate that it may exert contrasting effects on the efficacy of chemotherapeutic treatments when given as dietary supplement, being in that case harmful for patients. This dual role of α-tocopherol and, in particular, its effects on the efficacy of anticancer drugs remains poorly documented. For this purpose, we studied here, using high throughput flow cytometry, the direct impact of α-tocopherol on apoptosis and cell cycle arrest induced by different cytotoxic agents on various models of cancer cell lines in vitro. Our results indicate that physiologically relevant concentrations of α-tocopherol strongly compromise the cytotoxic and cytostatic action of various protein kinase inhibitors (KI), while other classes of chemotherapeutic agents or apoptosis inducers are unaffected by this vitamin. Interestingly, these anti-chemotherapeutic effects of α-tocopherol appear to be unrelated to its antioxidant properties since a variety of other antioxidants were completely neutral toward KI-induced cell cycle arrest and cell death. In conclusion, our data suggest that dietary α-tocopherol could limit KI effects on tumour cells, and, by extent, that this could result in a reduction of the clinical efficacy of anti-cancer treatments based on KI molecules.
Asunto(s)
Antineoplásicos , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Vitaminas , alfa-Tocoferol , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacología , Suplementos Dietéticos/efectos adversos , Antagonismo de Drogas , Células HeLa , Humanos , Neoplasias/patología , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Vitaminas/antagonistas & inhibidores , Vitaminas/farmacología , alfa-Tocoferol/antagonistas & inhibidores , alfa-Tocoferol/farmacologíaRESUMEN
Kinase targets are being pursued in a variety of diseases beyond cancer, including immune and metabolic as well as viral, parasitic, fungal and bacterial. In particular, there is a relatively recent interest in kinase and ATP-binding targets in Mycobacterium tuberculosis in order to identify inhibitors and potential drugs for essential proteins that are not targeted by current drug regimens. Herein, we report the high throughput screening results for a targeted library of approximately 26,000 compounds that was designed based on current kinase inhibitor scaffolds and known kinase binding sites. The phenotypic data presented herein may form the basis for selecting scaffolds/compounds for further enzymatic screens against specific kinase or other ATP-binding targets in Mycobacterium tuberculosis based on the apparent activity against the whole bacteria in vitro.
Asunto(s)
Antituberculosos/farmacología , Factores Inmunológicos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Factores Inmunológicos/antagonistas & inhibidores , Mycobacterium tuberculosis/genética , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas , Tuberculosis Resistente a Múltiples Medicamentos/genéticaRESUMEN
"Shoot the driver" is the paradigm of targeted cancer therapy. However, resistance to targeted inhibitors of signaling pathways is a major problem. In part the redundancy of signaling networks can bypass targeted inhibitors and thereby reduce their biological effect. In this case the driver turns out to be one of several potential messengers and is easily replaced. Cocktails of multiple targeted inhibitors are an obvious solution. This is limited, however, by the lack of potent inhibitors and may also produce increased toxicity. Therefore we explored the direct blockade of a key biological activity downstream from multiple converging oncogenic signals. Specifically, several oncogenic signaling pathways including AKT, MAPK and PIM kinase signals converge on the activation of cap-dependent translation. In cancer cells, aberrant activation of cap-dependent translation favors the increased expression of short-lived oncoproteins like c-MYC, MCL1, CYCLIN D1 and the PIM kinases. Intriguingly, cancer cells are especially sensitive to even temporary reductions in these proteins. We will discuss our findings concerning translational inhibitor therapy in cancer.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Animales , Antineoplásicos , Resistencia a Antineoplásicos , Humanos , Imidazoles/farmacología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/metabolismo , Ratones , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Piridazinas/farmacología , Triterpenos/uso terapéuticoRESUMEN
Biological agents induce cutaneous adverse drug reactions (CADR) different from those observed with xenobiotics. Type alpha is the cytokine release syndrome, type beta are hypersensitivity reactions and type gamma is a cytokine imbalance syndrome. Infusion-reactions, anaphylactoid reactions occur with various biological agents administered intravenously. In non-severe cases the infusion rate has to be reduced, in severe reactions, the treatment must be stopped and resuscitation carried out with corticosteroids and epinephrine. Reactions may be due to an alpha syndrome but a true allergy could be involved as demonstrated in some patients with IgE antibodies to the galactose-alpha-1,3-galactose portion of the cetuximab or anti infliximab-IgE. Some desensitisation protocols have been published. Non allergic itching and eczema-like lesions are frequent with epidermal growth factor receptor inhibitors. Rash or desquamation was observed in 40% of cases with antiangiogenic agents, 90% of patients treated with imatinib have rashes, oedema or pruritus and a non-allergic periorbital oedema. Severe CADR, such as Stevens-Johnson syndrome, can be provoked. Delayed readings of intradermal tests could be of value in managing patients with a maculopapular rash due to interferon. Anaphylaxis attributed to omalizumab seems to be rare (0.2%) and skin rashes occur in 7% of cases. Anaphylactoid reactions occur in 1% of patients treated with natalizumab. In the case of anti-natalizumab antibody-mediated reactions, treatment should be stopped. These allergic-like side effects of new biological agents must be known and reported to Pharmacovigilance agency networks.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Hipersensibilidad a las Drogas/terapia , Hipersensibilidad Tardía/terapia , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anafilaxia/inducido químicamente , Anticuerpos Antiidiotipos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Benzamidas , Bencenosulfonatos/efectos adversos , Cetuximab , Hipersensibilidad a las Drogas/inmunología , Eccema/inducido químicamente , Receptores ErbB/antagonistas & inhibidores , Humanos , Hipersensibilidad Tardía/inmunología , Mesilato de Imatinib , Indoles/efectos adversos , Infliximab , Natalizumab , Niacinamida/análogos & derivados , Omalizumab , Compuestos de Fenilurea , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Piridinas/efectos adversos , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Rituximab , Sorafenib , SunitinibRESUMEN
Isothiazolidinone (IZD) heterocycles can act as effective components of protein tyrosine phosphatase (PTP) inhibitors by simultaneously replicating the binding interactions of both a phosphoryl group and a highly conserved water molecule, as exemplified by the structures of several PTP1B-inhibitor complexes. In the first unambiguous demonstration of IZD interactions with a PTP other than PTP1B, it is shown by X-ray crystallography that the IZD motif binds within the catalytic site of the Yersinia pestis PTP YopH by similarly displacing a highly conserved water molecule. It is also shown that IZD-based bidentate ligands can inhibit YopH in a nonpromiscuous fashion at low micromolar concentrations. Hence, the IZD moiety may represent a useful starting point for the development of YopH inhibitors.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/química , Materiales Biomiméticos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Fosfatasas/química , Tiazoles/química , Yersinia pestis/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Materiales Biomiméticos/metabolismo , Cristalografía por Rayos X , Modelos Moleculares , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Relación Estructura-Actividad , Tiazoles/antagonistas & inhibidores , Tiazoles/metabolismo , Yersinia pestis/metabolismoRESUMEN
In vitro exposure of Postnatal Day 4 (PND4) rat ovaries to the occupational chemical 4-vinylcyclohexene diepoxide (VCD) destroys specifically primordial and primary follicles via acceleration of atresia. Because oocyte-expressed c-kit (KIT) plays a critical role in follicle survival and activation, a direct interaction of VCD with KIT as its mechanism of ovotoxicity was investigated. PND4 rat ovaries were cultured with and without VCD (30 µM) for 2 days. When assessed by Western analysis or mobility shift detection, phosphorylated KIT (pKIT) was decreased (P < 0.05) by VCD exposure, while total KIT protein was unaffected. Anti-mouse KIT2 (ACK2) antibody binds KIT and blocks its signaling pathways, whereas anti-mouse KIT 4 (ACK4) antibody binds KIT but does not block its activity. PND4 rat ovaries were incubated for 2 days with and without VCD with and without ACK2 (80 µg/ml) or ACK4 (80 µg/ml). ACK2 decreased pKIT; however, ACK4 had no effect. Conversely, ACK2 did not affect a VCD-induced decrease in pKIT, whereas ACK4 further reduced it. Because ACK2 and ACK4 (known to directly bind KIT) affect VCD responses, these results support the fact that VCD interacts directly with KIT. The effect of these antibodies on VCD-induced follicle loss was measured after 8 days of incubation. ACK2 further reduced (P < 0.05) VCD-induced follicle loss, whereas ACK4 did not affect it. These findings demonstrate that VCD induces ovotoxicity by direct inhibition of KIT autophosphorylation of the oocyte. The data also further support the vital function of KIT and its signaling pathway in primordial follicle survival and activation, as well as its role in VCD-induced ovotoxicity.
Asunto(s)
Ciclohexenos/toxicidad , Contaminantes Ambientales/toxicidad , Ovario/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Compuestos de Vinilo/toxicidad , Animales , Animales Recién Nacidos , Anticuerpos Bloqueadores/metabolismo , Reacciones Antígeno-Anticuerpo/efectos de los fármacos , Ciclohexenos/antagonistas & inhibidores , Contaminantes Ambientales/antagonistas & inhibidores , Femenino , Atresia Folicular/efectos de los fármacos , Ligandos , Terapia Molecular Dirigida , Peso Molecular , Técnicas de Cultivo de Órganos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/metabolismo , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/agonistas , Proteínas Proto-Oncogénicas c-kit/química , Proteínas Proto-Oncogénicas c-kit/metabolismo , Ratas , Ratas Endogámicas F344 , Compuestos de Vinilo/antagonistas & inhibidoresRESUMEN
S-Adenosyl-L-methionine (SAM) is one of the major methyl donors in all living organisms. The exogenous treatment with SAM leads to increased actinorhodin production in Streptomyces coelicolor A3(2). In this study, mutants from different stages of the AfsK-AfsR signal transduction cascade were used to test the possible target of SAM. SAM had no significant effect on actinorhodin production in afsK, afsR, afsS, or actII-open reading frame 4 (ORF4) mutant. This confirms that afsK plays a critical role in delivering the signal generated by exogenous SAM. The afsK-pHJL-KN mutant did not respond to SAM, suggesting the involvement of the C-terminal of AfsK in binding with SAM. SAM increased the in vitro autophosphorylation of kinase AfsK in a dose-dependent manner, and also abolished the effect of decreased actinorhodin production by a Ser/Thr kinase inhibitor, K252a. In sum, our results suggest that SAM activates actinorhodin biosynthesis in S. coelicolor M130 by increasing the phosphorylation of protein kinase AfsK.
Asunto(s)
Proteínas Serina-Treonina Quinasas/metabolismo , S-Adenosilmetionina/farmacología , Streptomyces coelicolor/metabolismo , Antraquinonas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Carbazoles/antagonistas & inhibidores , Carbazoles/farmacología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Alcaloides Indólicos/antagonistas & inhibidores , Alcaloides Indólicos/farmacología , Mutación , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/efectos de los fármacos , Streptomyces coelicolor/citología , Streptomyces coelicolor/enzimología , Streptomyces coelicolor/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Leptin produced by the placental syncytiotrophoblasts participates in a number of processes in pregnancy including implantation, proliferation of the cytotrophoblasts, and nutrient transfer across the placenta. Despite the functional significance of leptin in pregnancy, the regulation of leptin synthesis is poorly understood in human placental syncytiotrophoblasts. In this study, we investigated the role of endogenous human chorionic gonadotropin (hCG) in the regulation of leptin production as well as the underlying mechanism involving the cross talk between cAMP and p38 mitogen-activated protein kinase (MAPK) pathways. We found that neutralization of endogenous hCG with its antibody dose dependently decreased leptin mRNA level and secretion, whereas exogenous hCG increased leptin mRNA level and secretion. Activation of the cAMP pathway with dibutyryl cAMP (db cAMP) or forskolin recapitulated the stimulatory effect of hCG on leptin expression. Inhibition of protein kinase A with H89 not only reduced the basal leptin expression but also attenuated the induced leptin expression by hCG. Treatment of the syncytiotrophoblasts with db cAMP and hCG phosphorylated p38 MAPK. Inhibition of p38 MAPK with SB203580 not only reduced the basal leptin production but also attenuated the leptin-induced production by both hCG and db cAMP. These data suggest that endogenous hCG plays a significant role in maintaining leptin production in human placental syncytiotrophoblasts, and this effect involves a cross talk between cAMP and p38 MAPK pathways.
Asunto(s)
Gonadotropina Coriónica/metabolismo , AMP Cíclico/metabolismo , Leptina/metabolismo , Sistema de Señalización de MAP Quinasas , Sistemas de Mensajero Secundario , Trofoblastos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Células Cultivadas , Gonadotropina Coriónica/antagonistas & inhibidores , AMP Cíclico/agonistas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Leptina/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Concentración Osmolar , Fosforilación/efectos de los fármacos , Placenta/citología , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Sistemas de Mensajero Secundario/efectos de los fármacos , Trofoblastos/citología , Trofoblastos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
To elucidate the role of Na(+)/Ca(2+) exchanger (NCX) in neurite outgrowth, we investigated the effects of NCX inhibitors on neurite outgrowth in PC12 cells. KB-R7943 and 3',4'-dichlorobenzamil, NCX inhibitors, inhibited the neurite outgrowth caused by nerve growth factor (NGF). NCX inhibitors inhibited the neurite outgrowth caused by dibutylyl cAMP, which rapidly reorganizes the cytoskeleton. KB-R7943 inhibited the neurite outgrowth caused by Y-27632, an inhibitor of Rho kinase (ROCK) that regulates actin. However, NCX inhibitors did not inhibit NGF-induced phosphorylation of extracellular signal-regulated kinase. These results suggest that NCX inhibitor affects downstream of the Rho-ROCK signal transduction pathways in neurite outgrowth.
Asunto(s)
Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuritas/efectos de los fármacos , Neuronas/efectos de los fármacos , Intercambiador de Sodio-Calcio/antagonistas & inhibidores , Amidas/antagonistas & inhibidores , Amidas/farmacología , Amilorida/análogos & derivados , Amilorida/farmacología , Animales , Bucladesina/antagonistas & inhibidores , Bucladesina/farmacología , Citoesqueleto/efectos de los fármacos , Microscopía de Contraste de Fase , Factor de Crecimiento Nervioso/antagonistas & inhibidores , Factor de Crecimiento Nervioso/metabolismo , Neuritas/metabolismo , Neuritas/ultraestructura , Neuronas/metabolismo , Neuronas/ultraestructura , Concentración Osmolar , Células PC12 , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/antagonistas & inhibidores , Piridinas/farmacología , Ratas , Tiourea/análogos & derivados , Tiourea/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de la Membrana/fisiología , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Carbazoles/farmacología , Carbazoles/uso terapéutico , Células Cultivadas , Antagonismo de Drogas , Furanos , Humanos , Indazoles/farmacología , Indazoles/uso terapéutico , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/farmacología , Estudios Multicéntricos como Asunto , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piperazinas/farmacología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sorafenib , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Estaurosporina/uso terapéutico , Resultado del TratamientoRESUMEN
Plasmodium falciparum, Leishmania, Trypanosomes, are the causers of diseases such as malaria, leishmaniasis and African trypanosomiasis that nowadays are the most serious parasitic health problems worldwide. The great number of deaths and the few drugs available against these parasites, make necessary the search for new drugs. Some of these antiparasitic drugs also are GSK-3 inhibitors. GSKI-3 are candidates to develop drugs for the treatment of Alzheimer's disease. In this work topological descriptors for a large series of 3,370 active/non-active compounds were initially calculated with the ModesLab software. Linear Discriminant Analysis was used to fit the classification function and it predicts heterogeneous series of compounds like paullones, indirubins, meridians, etc. This study thus provided a general evaluation of these types of molecules.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antiparasitarios/farmacología , Biología Computacional/métodos , Evaluación Preclínica de Medicamentos/métodos , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad Cuantitativa , Enfermedad de Alzheimer/enzimología , Antiparasitarios/química , Análisis Discriminante , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
PURPOSE OF REVIEW: The pathophysiology of Philadelphia-chromosome negative myeloproliferative disorders has significantly advanced with the discovery of JAK2V617F. The prevalence of JAK2V617F mutation has made it a much anticipated target for inhibition; this review will update and assess progress. RECENT FINDINGS: Many agents have been studied in preclinical trials, of which few have entered clinical trials. Data from the clinical trials are limited and mostly in the form of abstracts and reviews. SUMMARY: The prevalence of the JAK2V617F mutation in the classic Philadelphia-chromosome negative myeloproliferative disorders has made it a much anticipated target for inhibition. Present in greater than 90% of patients with polycythemia vera and approximately 50% of patients with essential thrombocythemia and primary myelofibrosis, it has been hoped that targeted inhibition of JAK2V617F would achieve similar disease control as imatinib mesylate has produced in chronic myeloid leukemia. However, JAK2V617F in the Philadelphia-chromosome negative myeloproliferative disorders, unlike bcr/abl tyrosine kinase in chronic myeloid leukemia, is not a causative but rather a secondary somatic mutation. As the JAK2 inhibitors move into phase III clinical trials, their efficacy and role in therapy is becoming clearer; however, there are still many questions needing answers.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/fisiopatología , Inhibidores de Proteínas Quinasas/antagonistas & inhibidoresRESUMEN
PURPOSE: Gefitinib is a valid second-line therapy for previously treated non-small cell lung cancer (NSCLC) patients. The influences of various chemotherapy regimens and EGFR mutations on effectiveness of second-line gefitinib are not clear, and laboratory studies revealed that previous chemotherapy changed the effectiveness of treatment with gefitinib. In order to clarify the factors changing the effectiveness of second-line gefitinib, we performed a retrospective analysis of the prognosis of NSCLC patients who received gefitinib after first-line chemotherapy. DESIGN: We analyzed the clinical data and mutational studies of NSCLC patients with EGFR mutations from the National Taiwan University Hospital. RESULTS: One hundred and two previously treated patients received second-line gefitinib for stage IIIB or IV NSCLC. Fifty of all the 102 patients were sequenced for EGFR status. Twenty-eight had EGFR mutation and 22 had wild type EGFR. The response rate and progression-free survival of second-line gefitinib was not changed by different previous chemotherapy regimens. The potent factor with regards to the effectiveness of second-line gefitinib was EGFR mutation which led to a better response rate and longer progression-free survival of gefitinib than wild type EGFR. CONCLUSIONS: Gefitinib is effective as a second-line therapy for previously treated NSCLC patients. The effectiveness was influenced by EGFR status rather than previous chemotherapy regimens.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Supervivencia sin Enfermedad , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Estudios RetrospectivosRESUMEN
Genetic aberrations (lesions) govern the transformation of previously normal cells into cancer cells by changing key signaling pathways within the cells that control cellular proliferation, differentiation and survival. Such lesions are thus considered prime molecular targets for cancer therapy. While some notable examples underscore the clinical relevance of this connection between genetics and drug response, there is a lack of analytical approaches to provide such novel "drug-mutation" combinations in a broad and unbiased fashion. We have therefore collected a panel of genetically and phenotypically characterized nonsmall cell lung cancer (NSCLC) cell lines to systematically screen for drug susceptibility of NSCLC as a function of genetic lesions. We found such genetic lesions to predict activity of geldanamycin-derived Hsp90 inhibitors as well as of the clinically approved SRC/ABL-inhibitor dasatinib. This work may therefore help advancing our understanding of critical oncogenic pathway dependencies and may impact future drug development by defining drug-susceptible patient populations.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Transformación Celular Neoplásica/genética , Mutación/genética , Transducción de Señal/efectos de los fármacos , Benzoquinonas/farmacología , Línea Celular Tumoral , Dasatinib , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Lactamas Macrocíclicas/farmacología , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Transducción de Señal/genética , Tiazoles/farmacologíaRESUMEN
The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, recently emerged as a major player and candidate drug target for human autoimmunity. The enzyme includes a classical N-terminal protein tyrosine phosphatase catalytic domain and a C-terminal PEST-enriched domain, separated by an approximately 300-amino acid interdomain. Little is known about the regulation of LYP. Herein, by analysis of serial truncation mutants of LYP, we show that the phosphatase activity is strongly inhibited by protein regions C-terminal to the catalytic domain. We mapped the minimal inhibitory region to the proximal portion of the interdomain. We show that the activity of LYP is inhibited by an intramolecular mechanism, whereby the proximal portion of the interdomain directly interacts with the catalytic domain and reduces its activity.
Asunto(s)
Dominio Catalítico/fisiología , Linfocitos/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 22/fisiología , Secuencia de Aminoácidos , Activación Enzimática , Humanos , Células Jurkat , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 22/química , Proteína Tirosina Fosfatasa no Receptora Tipo 22/metabolismoRESUMEN
By interfering with signal transduction events that control cell proliferation and fate, kinase inhibitors (KIs) hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in off-target cells could lead to side effects. For instance, this context dependence renders many KIs potentially cardiotoxic since inhibition of primary cancer targets such as ABL, RAF1 or AMPK recruits pro-apoptotic pathways in cardiomyocytes. Motivated by these observations, we propose a mode of 'therapeutic editing' where one drug (the editor) suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, and the editor suppresses the downstream propagation of toxicity-related signaling.