Dual Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer

Yu Hsuan Chen, Ming Feng Wei, Chun Wei Wang, Hsiao Wei Lee, Shiow Lin Pan, Ming Gao, Sung Hsin Kuo, Ann Lii Cheng, Che Ming Teng

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)582-590
Number of pages9
JournalCancer Letters
Volume357
Issue number2
DOIs
Publication statusPublished - Feb 28 2015
Externally publishedYes

Fingerprint

1-Phosphatidylinositol 4-Kinase
Sirolimus
Colorectal Neoplasms
Radiation
Neoplasms
HCT116 Cells
HT29 Cells
Double-Stranded DNA Breaks
dactolisib
Radiation Tolerance
Radiation Effects
G1 Phase
Phosphatidylinositol 3-Kinases
Cell Survival
Cell Count
DNA

Keywords

  • BEZ235
  • Colorectal cancer
  • PI3K/Akt/mTOR
  • Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Dual Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer. / Chen, Yu Hsuan; Wei, Ming Feng; Wang, Chun Wei; Lee, Hsiao Wei; Pan, Shiow Lin; Gao, Ming; Kuo, Sung Hsin; Cheng, Ann Lii; Teng, Che Ming.

In: Cancer Letters, Vol. 357, No. 2, 28.02.2015, p. 582-590.

Research output: Contribution to journalArticle

Chen, Yu Hsuan ; Wei, Ming Feng ; Wang, Chun Wei ; Lee, Hsiao Wei ; Pan, Shiow Lin ; Gao, Ming ; Kuo, Sung Hsin ; Cheng, Ann Lii ; Teng, Che Ming. / Dual Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer. In: Cancer Letters. 2015 ; Vol. 357, No. 2. pp. 582-590.
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