Cancer Res Treat.  2019 Apr;51(2):451-463. 10.4143/crt.2017.341.

Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells

Affiliations
  • 1Cancer Research Institute, Seoul National University, Seoul, Korea. moisa@snu.ac.kr
  • 2Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
  • 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Abstract

PURPOSE
Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells.
MATERIALS AND METHODS
The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis.
RESULTS
AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines.
CONCLUSION
Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.

Keyword

AZD1208; Pim kinase inhibitor; Autophagy; Akt; Stomach neoplasms

MeSH Terms

Apoptosis
Autophagy
Blotting, Western
Cell Cycle
Cell Death
Cell Line
Cell Proliferation
Cell Survival
DNA Damage
Fluorescent Antibody Technique
Humans
Phosphotransferases*
Protein Isoforms
Stomach Neoplasms*
Phosphotransferases
Protein Isoforms
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