Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Bases de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Cancer Lett ; 400: 161-174, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28450161

RESUMEN

The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene. The responses of various tumor cell lines to treatment with either compound were characterized in the presence or absence of supplemental pyruvate or antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH). Drug effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity were investigated by mass spectrometric analysis. The development of 3-BP resistance was investigated in MCT-1-positive HCT116 colon carcinoma cells in vitro. Our results show that NEO218: (i) pyruvylated GAPDH on all 4 of its cysteine residues and shut down enzymatic activity; (ii) severely lowered cellular ATP content below life-sustaining levels, and (iii) triggered rapid necrosis. Intriguingly, supplemental antioxidants effectively prevented cytotoxic activity of NEO218 as well as 3-BP, but supplemental pyruvate powerfully protected cells only from 3-BP, not from NEO218. Unlike 3-BP, NEO218 exerted its potent cytotoxic activity irrespective of cellular MCT-1 status. Treatment of HCT116 cells with 3-BP resulted in prompt development of resistance, based on the emergence of MCT-1-negative cells. This was not the case with NEO218, and highly 3-BP-resistant cells remained exquisitely sensitive to NEO218. Thus, our study identifies a mechanism by which tumor cells develop rapid resistance to 3-BP, and presents NEO218 as a superior agent not subject to this cellular defense. Furthermore, our results offer alternative interpretations of previously published models on the role of supplemental antioxidants: Rather than quenching reactive oxygen species (ROS), supplemental NAC or GSH directly interact with 3-BP, thereby neutralizing the drug's cytotoxic potential before it can trigger ROS production. Altogether, our study introduces new aspects of the cytotoxic mechanism of 3-BP, and characterizes NEO218 as an analog able to overcome a key cellular defense mechanism towards this drug.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Monoterpenos/farmacología , Neoplasias/tratamiento farmacológico , Piruvatos/farmacología , Simportadores/metabolismo , Adenosina Trifosfato/metabolismo , Alquilación , Antioxidantes/farmacología , Relación Dosis-Respuesta a Droga , Gliceraldehído-3-Fosfato Deshidrogenasas , Glucólisis/efectos de los fármacos , Células HCT116 , Humanos , Células MCF-7 , Transportadores de Ácidos Monocarboxílicos/genética , Necrosis , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Simportadores/genética , Transfección
2.
J Med Chem ; 54(8): 2902-14, 2011 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-21443194

RESUMEN

Herein, we discovered a series of propynoic acid carbamoyl methyl-amides (PACMAs) with potent cytotoxicity against a panel of cancer cell lines. These compounds interrupted cell cycle progression at low micromolar concentrations and induced early and late stage apoptosis. A representative compound suppressed tumor growth without apparent toxicity in an MDA-MB-435 mouse xenograft model. We used a Kinexus 628-antibody microarray and the Ingenuity Pathway Analysis (IPA) bioinformatics tools to better understand their mechanisms. The IPA analysis revealed the initiation of Nrf2-mediated oxidative stress through modulating the expression of SOD1 and STIP1 by compound 1. The involvement of the oxidative stress pathway was further validated by measuring the levels of the PACMA-induced mitochondrial superoxide species. To our knowledge, this is the first report on the discovery and biological evaluations of PACMAs as anticancer agents. Their broad-spectrum in vitro cytotoxicity, possibly through an oxidative stress-mediated pathway, and in vivo efficacy warrant further preclinical investigations.


Asunto(s)
Alquinos/farmacología , Amidas/química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Propionatos/farmacología , Alquinos/química , Alquinos/farmacocinética , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Caspasa 9/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Estrés Oxidativo , Propionatos/química , Propionatos/farmacocinética , Proteína p53 Supresora de Tumor/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA