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

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.

• Authors: Mintao Mao, Yumei Liu, Xinhai Gao
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 490 Issue 4 Pg. 1244-1249 (09 02 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28676397 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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