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Cancer Lett ; 400: 161-174, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28450161


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.

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
Hum Gene Ther ; 26(2): 82-93, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25419577


Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.

Neoplasias Encefálicas/terapia , Citosina Desaminasa/genética , Proteínas Fúngicas/genética , Terapia Genética/métodos , Vectores Genéticos/farmacocinética , Glioma/terapia , Retroviridae/genética , Animales , Anticuerpos Neutralizantes/análisis , Antimetabolitos/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Ensayos Clínicos como Asunto , Citosina Desaminasa/metabolismo , Citosina Desaminasa/farmacocinética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Flucitosina/farmacología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/farmacocinética , Expresión Génica , Genes Reporteros , Vectores Genéticos/administración & dosificación , Vectores Genéticos/química , Glioma/genética , Glioma/mortalidad , Glioma/patología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inyecciones Intravenosas , Ratones , Ratones Desnudos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Retroviridae/inmunología , Análisis de Supervivencia , Distribución Tisular
Curr Pharm Des ; 17(23): 2428-38, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21827419


The endoplasmic reticulum (ER) stress response represents a cellular "yin-yang" process, where low to moderate activity is cell protective and supports chemoresistance (yang), but where more severe conditions will aggravate these mechanisms to the point where they abandon their protective efforts and instead turn on a cell death program (yin). Because tumor cells frequently experience chronic stress conditions (due to hypoxia, hypoglycemia, acidification, etc.), the protective yang components of their ER stress response are continuously engaged and thus less able to neutralize additional insults taxing the ER stress response. This tumor-specific situation may provide therapeutic opportunities for pharmacologic intervention, where further aggravation of ER stress would lead to the activation of pro-apoptotic yin components and result in tumor cell death. This review will describe the yin-yang principle of ER stress, and will present pharmacologic agents and combination strategies aimed at exploiting the ER stress response for improved therapeutic outcomes, particularly in the setting of difficult to treat tumor types such as glioblastoma.

Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Diseño de Fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Yin-Yang , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/irrigación sanguínea , Glioblastoma/metabolismo , Humanos
Cancer Lett ; 302(2): 100-8, 2011 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-21257259


The alkylating agent temozolomide, in combination with surgery and radiation, is the current standard of care for patients with glioblastoma. However, despite this extensive therapeutic effort, the inclusion of temozolomide extends survival only by a few short months. Among the factors contributing to chemoresistance is elevated expression of the endoplasmic reticulum (ER) chaperone GRP78 (glucose-regulated protein 78; BiP), a key pro-survival component of the ER stress response system. Because the green tea component EGCG (epigallocatechin 3-gallate) had been shown to inhibit GRP78 function, we investigated whether this polyphenolic agent would be able to increase the therapeutic efficacy of temozolomide in preclinical models of glioblastoma. Mice with intracranially implanted human U87 (p53 wild type) or U251 (p53 mutant) glioblastoma cells were treated with temozolomide and EGCG, alone and in combination. We found that EGCG alone did not provide survival benefit, but significantly improved the existing therapeutic effect of temozolomide, i.e., life extension was substantially greater under combination therapy as compared to temozolomide therapy alone. Immunohistochemical analysis of tumor tissue revealed increased expression levels of GRP78 in temozolomide-treated animals, which was diminished when temozolomide was combined with EGCG. Parallel in vitro experiments with siRNA targeting GRP78 or its major pro-apoptotic antagonist CHOP (CCAAT/enhancer binding protein homologous protein/GADD153) further established a critical role of the ER stress response system, where si-GRP78 sensitized cells to treatment with temozolomide, and si-CHOP provided protection from drug-induced toxicity. Thus, ER stress-regulatory components affect the chemotherapeutic response of glioblastoma cells to treatment with temozolomide, and inclusion of EGCG is able to increase the therapeutic efficacy of this DNA-damaging agent.

Neoplasias Encefálicas/tratamiento farmacológico , Camellia sinensis/química , Catequina/análogos & derivados , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/uso terapéutico , Catequina/uso terapéutico , Línea Celular Tumoral , Dacarbazina/uso terapéutico , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Chaperón BiP del Retículo Endoplásmico , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Temozolomida
Expert Opin Investig Drugs ; 17(2): 197-208, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18230053


Celecoxib is an NSAID that was developed as a selective inhibitor of COX-2 and approved by the FDA for the treatment of various forms of arthritis and the management of acute or chronic pain. In addition, it was more recently approved as an oral adjunct to prevent colon cancer development in patients with familial adenomatous polyposis and is presently being investigated for its chemotherapeutic potential in the therapy of advanced cancers. However, in laboratory studies it was discovered that celecoxib was able to suppress tumor growth in the absence of any apparent involvement of COX-2, and additional pharmacologic activities associated with this drug were found. Intriguingly, the two pharmacologic effects, inhibition of COX-2 and suppression of tumor growth, were found to reside in different structural aspects of the celecoxib molecule and, therefore, could be separated. This dualism enabled the synthesis of close structural analogs of celecoxib that exhibited increased antitumor potency in the absence of COX-2 inhibition. In theory, such compounds should be superior to celecoxib for antitumor purposes because they might reduce gastrointestinal and cardiovascular risks and the life-threatening side effects that appear during the long-term use of selective COX-2 inhibitors. In this review, the authors present the status of preclinical development of anticancer analogs of celecoxib that are COX-2 inactive, with an emphasis on 2,5-dimethyl-celecoxib (DMC) and OSU-03012.

Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Pirazoles/farmacología , Sulfonamidas/farmacología , Animales , Antineoplásicos/farmacocinética , Celecoxib , Ciclooxigenasa 2 , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Pirazoles/farmacocinética , Sulfonamidas/farmacocinética