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JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma.
Garcia, Patrick L; Miller, Aubrey L; Gamblin, Tracy L; Council, Leona N; Christein, John D; Arnoletti, J Pablo; Heslin, Marty J; Reddy, Sushanth; Richardson, Joseph H; Cui, Xiangqin; van Waardenburg, Robert C A M; Bradner, James E; Yang, Eddy S; Yoon, Karina J.
Afiliação
  • Garcia PL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Miller AL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Gamblin TL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Council LN; Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Christein JD; The Birmingham Veterans Administration Medical Center, Birmingham, Alabama.
  • Arnoletti JP; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
  • Heslin MJ; Department of Surgery, Division of Surgical Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Reddy S; Department of Surgery, Division of Surgical Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Richardson JH; Department of Surgery, Division of Surgical Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Cui X; Department of Surgery, Division of Surgical Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
  • van Waardenburg RCAM; Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama.
  • Bradner JE; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
  • Yang ES; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Yoon KJ; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Mol Cancer Ther ; 17(1): 107-118, 2018 01.
Article em En | MEDLINE | ID: mdl-29142067
ABSTRACT
Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ∼8 months. Combining this agent with cisplatin increases survival by ∼3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA. Mol Cancer Ther; 17(1); 107-18. ©2017 AACR.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azepinas / Triazóis / Neoplasias dos Ductos Biliares / Colangiocarcinoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azepinas / Triazóis / Neoplasias dos Ductos Biliares / Colangiocarcinoma Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article