| Autor: |
Miller AL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Garcia PL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Fehling SC; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Gamblin TL; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Vance RB; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Council LN; Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; The Birmingham Veterans Administration Medical Center, Birmingham, AL 35233, USA., Chen D; Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USA., Yang ES; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA., van Waardenburg RCAM; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Yoon KJ; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. |
| Abstrakt: |
Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models ( P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine. |
