Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells

Biochem Biophys Res Commun. 2017 Sep 2;490(4):1244-1249. doi: 10.1016/j.bbrc.2017.07.002. Epub 2017 Jul 1.

Abstract

The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity.

Keywords: Autophagy; Colorectal cancer; DNA-PKcs; Ku-0060648; PI3K-AKT-mTOR.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects*
  • Cell Proliferation / drug effects
  • Chromones / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology*
  • Drug Screening Assays, Antitumor
  • Humans
  • Structure-Activity Relationship
  • Thiophenes / pharmacology*
  • Tumor Cells, Cultured

Substances

  • 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo(b,d)thiophen-1-yl)acetamide
  • Antineoplastic Agents
  • Chromones
  • Thiophenes