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1.
Blood ; 127(7): 858-68, 2016 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-26603836

RESUMEN

Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Núcleo Celular/metabolismo , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Neoplásico/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/patología , Humanos , Linfoma de Células B/patología , Proteínas de Neoplasias/metabolismo
2.
Bioorg Med Chem Lett ; 28(17): 3004-3008, 2018 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-30061030

RESUMEN

KCNQ (Kv7) has emerged as a validated target for the development of novel anti-epileptic drugs. In this paper, a series of novel N-phenylbutanamide derivatives were designed, synthesized and evaluated as KCNQ openers for the treatment of epilepsy. These compounds were evaluated for their KCNQ opening activity in vitro and in vivo. Several compounds were found to be potent KCNQ openers. Compound 1 with favorable in vitro activity was submitted to evaluation in vivo. Results showed that compound 1 owned significant anti-convulsant activity with no adverse effects. It was also found to posses favorable pharmacokinetic profiles in rat. This research may provide novel potent compounds for the discovery of KCNQ openers in treating epilepsy.


Asunto(s)
Diseño de Fármacos , Epilepsia/tratamiento farmacológico , Canales de Potasio KCNQ/antagonistas & inhibidores , Fenilbutiratos/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Epilepsia/metabolismo , Prueba de Esfuerzo , Canales de Potasio KCNQ/metabolismo , Ratones , Estructura Molecular , Fenilbutiratos/síntesis química , Fenilbutiratos/química , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular
3.
Bioorg Med Chem Lett ; 28(10): 1731-1735, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29706422

RESUMEN

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.


Asunto(s)
Anticonvulsivantes/farmacología , Diseño de Fármacos , Epilepsia/tratamiento farmacológico , Canales de Potasio KCNQ/antagonistas & inhibidores , Piperidinas/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Relación Dosis-Respuesta a Droga , Epilepsia/metabolismo , Humanos , Canales de Potasio KCNQ/metabolismo , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad
4.
Sci Adv ; 7(45): eabg1964, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34739311

RESUMEN

Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.

5.
Clin Epigenetics ; 8: 79, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27453763

RESUMEN

BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.


Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Decitabina , Epigénesis Genética/efectos de los fármacos , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/farmacología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Vorinostat
6.
J Clin Invest ; 126(9): 3351-62, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27482887

RESUMEN

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Indoles/farmacología , Ligandos , Linfoma de Células B Grandes Difuso/patología , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones SCID , Trasplante de Neoplasias , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Tiazolidinedionas/farmacología , Translocación Genética
7.
Cancer Discov ; 3(9): 1002-19, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23955273

RESUMEN

UNLABELLED: Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs. SIGNIFICANCE: The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL.


Asunto(s)
Azacitidina/uso terapéutico , Metilación de ADN/genética , Metilasas de Modificación del ADN/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/efectos adversos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Metilasas de Modificación del ADN/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Humanos , Persona de Mediana Edad , Interferencia de ARN , ARN Interferente Pequeño , Proteína Smad1/genética , Adulto Joven
8.
Se Pu ; 22(6): 630-3, 2004 Nov.
Artículo en Zh | MEDLINE | ID: mdl-15807118

RESUMEN

In order to improve the chiral separation capability of the conventional beta-cyclodextrin bonded-silica gel stationary phase, 2,6-di-O-pentyl-beta-cyclodextrin bonded stationary phase (PCDS) was prepared via a long spacer. The resulted bonded-silica stationary phase was characterized by three methods, namely Fourier transform infrared, Molisch color reaction, X-ray optical electrical energy spectrogram. The chromatographic performances of PCDS were investigated by using liquid chromatography with toluene, dimethyl phthalate, and phenanthrene as solutes, and their retention mechanism was investigated and discussed. The results show that the introduction of pentyl to beta-cyclodextrin leads to enhancement of the retention of the solutes. The chiral separation capability of the new bonded-silica stationary phase was evaluated by using liquid chromatography with some chiral drugs. Some of the enantiomers such as chlorphenamine maleate and bupropion hydrochloride were separated by heptakis (2,6-di-O-pentyl)-beta-cyclodextrin bonded silica stationary.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , beta-Ciclodextrinas/química , Gel de Sílice , Dióxido de Silicio/química
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