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Title: AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo

Abstract

The AGC kinase family is important cell proliferation and survival. Dysregulation of this family contributes to gastric cancer progression. Here, we evaluated the potential activity of AT13148, a first-in-class multi-AGC kinase inhibitor, against gastric cancer cells. Our results showed that AT13148 exerted potent cytotoxic and anti-proliferative activities against a panel human gastric cancer cell lines (HGC-27, AGS, SNU-601, N87 and MKN-28), possibly via inducing cancer cell apoptotic death. Apoptosis inhibition by the Caspase blockers dramatically attenuated AT13148-caused cytotoxicity against gastric cancer cells. Intriguingly, same AT13148 treatment was not cytotoxic/pro-apoptotic to the non-cancerous human gastric epithelial GEC-1 cells. At the signaling level, AT13148 treatment in gastric cancer cells dramatically suppressed activation of multiple AGC kinases, including Akt (at p-Thr-308), p70S6 kinase (p70S6K), glycogen synthase kinase 3β (GSK-3β) and p90 ribosomal S6 kinase (RSK). Our in vivo studies demonstrated that daily oral gavage of AT13148 at well-tolerated doses significantly inhibited HGC27 xenograft tumor growth in nude mice. AGC activity was also dramatically decreased in AT13148-administrated HGC27 tumors. Therefore, targeting AGC kinases by AT13148 demonstrates superior anti-gastric cancer activity both in vitro and in vivo. The preclinical results of this study support the progression of this molecule into future evaluation as a valuable anti-gastric cancer candidate. -more » Highlights: • AT13148 is cytotoxic and anti-proliferative to human gastric cancer cells. • AT13148 induces gastric cancer cell apoptotic death, inhibited by Caspase inhibitors. • AT13148 inactivates multiple AGC kinases in human gastric cancer cells. • AT13148 oral administration suppresses HGC27 xenograft growth in nude mice. • AT13148 oral administration inhibits multiple AGC kinases in HGC27 xenograft tumors.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [3];  [3]
  1. Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)
  2. (China)
  3. Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008 (China)
  4. Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008 (China)
  5. Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008 (China)
Publication Date:
OSTI Identifier:
22606217
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 478; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL PROLIFERATION; DEATH; GLYCOGEN; IN VITRO; IN VIVO; MICE; NEOPLASMS; ORAL ADMINISTRATION; PHOSPHOTRANSFERASES

Citation Formats

Xi, Yu, Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, Niu, Jianhua, Shen, Yun, Li, Dongmei, Peng, Xinyu, E-mail: pppengxinyu@sina.com, and Wu, Xiangwei, E-mail: wuxiangweiys@126.com. AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.01.167.
Xi, Yu, Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, Niu, Jianhua, Shen, Yun, Li, Dongmei, Peng, Xinyu, E-mail: pppengxinyu@sina.com, & Wu, Xiangwei, E-mail: wuxiangweiys@126.com. AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo. United States. doi:10.1016/J.BBRC.2016.01.167.
Xi, Yu, Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, Niu, Jianhua, Shen, Yun, Li, Dongmei, Peng, Xinyu, E-mail: pppengxinyu@sina.com, and Wu, Xiangwei, E-mail: wuxiangweiys@126.com. 2016. "AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo". United States. doi:10.1016/J.BBRC.2016.01.167.
@article{osti_22606217,
title = {AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo},
author = {Xi, Yu and Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008 and Niu, Jianhua and Shen, Yun and Li, Dongmei and Peng, Xinyu, E-mail: pppengxinyu@sina.com and Wu, Xiangwei, E-mail: wuxiangweiys@126.com},
abstractNote = {The AGC kinase family is important cell proliferation and survival. Dysregulation of this family contributes to gastric cancer progression. Here, we evaluated the potential activity of AT13148, a first-in-class multi-AGC kinase inhibitor, against gastric cancer cells. Our results showed that AT13148 exerted potent cytotoxic and anti-proliferative activities against a panel human gastric cancer cell lines (HGC-27, AGS, SNU-601, N87 and MKN-28), possibly via inducing cancer cell apoptotic death. Apoptosis inhibition by the Caspase blockers dramatically attenuated AT13148-caused cytotoxicity against gastric cancer cells. Intriguingly, same AT13148 treatment was not cytotoxic/pro-apoptotic to the non-cancerous human gastric epithelial GEC-1 cells. At the signaling level, AT13148 treatment in gastric cancer cells dramatically suppressed activation of multiple AGC kinases, including Akt (at p-Thr-308), p70S6 kinase (p70S6K), glycogen synthase kinase 3β (GSK-3β) and p90 ribosomal S6 kinase (RSK). Our in vivo studies demonstrated that daily oral gavage of AT13148 at well-tolerated doses significantly inhibited HGC27 xenograft tumor growth in nude mice. AGC activity was also dramatically decreased in AT13148-administrated HGC27 tumors. Therefore, targeting AGC kinases by AT13148 demonstrates superior anti-gastric cancer activity both in vitro and in vivo. The preclinical results of this study support the progression of this molecule into future evaluation as a valuable anti-gastric cancer candidate. - Highlights: • AT13148 is cytotoxic and anti-proliferative to human gastric cancer cells. • AT13148 induces gastric cancer cell apoptotic death, inhibited by Caspase inhibitors. • AT13148 inactivates multiple AGC kinases in human gastric cancer cells. • AT13148 oral administration suppresses HGC27 xenograft growth in nude mice. • AT13148 oral administration inhibits multiple AGC kinases in HGC27 xenograft tumors.},
doi = {10.1016/J.BBRC.2016.01.167},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 478,
place = {United States},
year = 2016,
month = 9
}
  • Highlights: Black-Right-Pointing-Pointer Zebularine inhibited cell growth of gastric cancer in a time- and dose-dependent manner. Black-Right-Pointing-Pointer Chromatin condensation and nuclear fragmentation were induced. Black-Right-Pointing-Pointer Zebularine promoted apoptosis via mitochondrial pathways. Black-Right-Pointing-Pointer Tumorigenicity was inhibited by zebularine. -- Abstract: DNA methyltransferase (DNMT) inhibitor zebularine has been reported to potentiate the anti-tumor effect by reactivating the expression of tumor suppressor genes and apoptosis-related genes in various malignant cells. However, the apoptotic signaling pathway in gastric cancer cells induced by zebularine is not well understood. In the study, the effects of zebularine on the growth and apoptosis of gastric cancer cells were investigatedmore » by MTT assay, Hoechst assay, Western blot analysis, flow cytometric analysis of annexin V-FITC/PI staining, and TUNEL assay. Zebularine was an effective inhibitor of human gastric cancer cells proliferation in vitro and in vivo. The effects were dose dependent. A zebularine concentration of 50 {mu}M accounted for the inhibition of cell proliferation of 67% at 48 h. The treatment with zebularine upregulated Bax, and decreased Bcl-2 protein. Caspase-3 was activated, suggesting that the apoptosis is mediated by mitochondrial pathways. Moreover, zebularine injection successfully inhibited the tumor growth via apoptosis induction which was demonstrated by TUNEL assay in xenograft tumor mouse model. These results demonstrated that zebularine induced apoptosis in gastric cancer cells via mitochondrial pathways, and zebularine might become a therapeutic approach for the treatment of gastric cancer.« less
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  • No abstract prepared.
  • In the present study, we tested the anti-pancreatic cancer activity by AT406, a small-molecule antagonist of IAP (inhibitor of apoptosis proteins). In established (Panc-1 and Mia-PaCa-2 lines) and primary human pancreatic cancer cells, treatment of AT406 significantly inhibited cell survival and proliferation. Yet, same AT406 treatment was non-cytotoxic to pancreatic epithelial HPDE6c7 cells. AT406 increased caspase-3/-9 activity and provoked apoptosis in the pancreatic cancer cells. Reversely, AT406′ cytotoxicity in these cells was largely attenuated with pre-treatment of caspase inhibitors. AT406 treatment caused degradation of IAP family proteins (cIAP1 and XIAP) and release of cytochrome C, leaving Bcl-2 unaffected in pancreaticmore » cancer cells. Bcl-2 inhibition (by ABT-737) or shRNA knockdown dramatically sensitized Panc-1 cells to AT406. In vivo, oral administration of AT406 at well-tolerated doses downregulated IAPs (cIAP1/XIAP) and inhibited Panc-1 xenograft tumor growth in severe combined immunodeficient (SCID) nude mice. Together, our preclinical results suggest that AT406 could be further evaluated as a promising anti-pancreatic cancer agent. - Highlights: • AT406 is cytotoxic to established/primary human pancreatic cancer cells. • AT406 provokes caspase-dependent apoptosis in pancreatic cancer cells. • AT406 causes degradation of key IAPs and promotes cytochrome C release. • Bcl-2 inhibition or knockdown dramatically sensitizes Panc-1 cells to AT406. • Oral administration of AT406 inhibits Panc-1 tumor growth in SCID nude mice.« less
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