title: Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer.
abstract: The present study was aimed to investigate whether combination of molecular targeting therapy, a dual PI3K/mTOR inhibitor (BEZ235), with radiation can enhance the radiosensitivity of colorectal cancer cells (CRC). K-RAS mutant CRC cells (HCT 116 and SW 620) and wild type CRC cells (HT 29) were irradiated with different dose of radiation (0-6 Gy). The synergistic effects of combining radiation with different concentration of BEZ235 (0-10 nM) pretreatment were demonstrated by cell survival assay. When comparing with radiation alone and BEZ235 alone, the combination of BEZ235 pretreatment and radiation resulted in an increased percentage of sub-G1 phase cells, and an increased number of γ-H2AX/cell (DNA double strand breaks). Radiation up-regulated AKT/mTOR signaling pathway, including the activation of phospho (p)-AKT, p-mTOR, p-eIF4E, and p-rpS6; and this activated AKT/mTOR signaling pathway was attenuated by BEZ235 pretreatment. In addition, BEZ235 blocked double strand break repair induced by radiation through attenuating the activation of ATM and DNA-PKcs and sensitized CRC cells to radiation. In vivo model, the tumor size and the expression pattern of p-mTOR, p-eIF4E, and p-rpS6 were significantly decreased in combined group than radiation alone or BEZ235 alone. Our findings indicate that the administration of BEZ235 before radiation enhances the radiotherapeutic effect of CRC cells both in vitro and in vivo.
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan; Pharmacological Institute, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Wei
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Pharmacological Institute, National Taiwan University, Taipei, Taiwan.
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: shkuo101@ntu.edu.tw.
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Cancer Research Center, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Pharmacological Institute, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D016513:Mice, SCID; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; C486377:AKTIP protein, human; C546842:MTOR protein, human; C531198:dactolisib
keywords: BEZ235; Colorectal cancer; PI3K/Akt/mTOR; Radiation