AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo
| Autor: | Xin-yu Peng, Xiang-wei Wu, Jian-hua Niu, Yu Xi, Dongmei Li, Yun Shen |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell Survival Biophysics Administration Oral Mice Nude Antineoplastic Agents Apoptosis Biology Biochemistry Mice 03 medical and health sciences Stomach Neoplasms GSK-3 Cell Line Tumor medicine Animals Humans Cytotoxic T cell Protein Kinase Inhibitors Molecular Biology Protein kinase B 2-Hydroxyphenethylamine Mice Inbred BALB C Dose-Response Relationship Drug Cell growth Kinase Cancer Cell Biology medicine.disease Cell biology Treatment Outcome 030104 developmental biology Cancer cell Cancer research Pyrazoles Female Protein Kinases |
| Zdroj: | Biochemical and Biophysical Research Communications. 478:330-336 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2016.01.167 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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