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Métodos Terapêuticos e Terapias MTCI
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1.
Mol Cancer Ther ; 16(9): 2035-2044, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28533437

RESUMO

There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% (P < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% (P = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. Mol Cancer Ther; 16(9); 2035-44. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Fluoruracila/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Instabilidade de Microssatélites , Mutação , Consumo de Oxigênio/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 35(12): 6639-53, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26637880

RESUMO

BACKGROUND/AIM: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2). MATERIALS AND METHODS: Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti-neoplastic drugs. RESULTS: We established a new in vitro model of hereditary PRCC2 - the NCCFH1 cell line. The cell line possesses a c.1162 delA - p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH(-/-) cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib. CONCLUSION: We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option.


Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase/metabolismo , Adolescente , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Humanos , Técnicas In Vitro , Masculino
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