دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo.
المؤلفون: Xi Y; Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China., Niu J; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China., Shen Y; Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China., Li D; Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China., Peng X; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China. Electronic address: pppengxinyu@sina.com., Wu X; Department of General Surgery, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China. Electronic address: wuxiangweiys@126.com.
المصدر: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2016 Sep 09; Vol. 478 (1), pp. 330-336. Date of Electronic Publication: 2016 Jan 30.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002- >: San Diego, CA : Elsevier
Original Publication: New York, Academic Press.
مواضيع طبية MeSH: 2-Hydroxyphenethylamine/*analogs & derivatives , Apoptosis/*drug effects , Cell Survival/*drug effects , Protein Kinases/*metabolism , Pyrazoles/*administration & dosage , Stomach Neoplasms/*drug therapy , Stomach Neoplasms/*metabolism, 2-Hydroxyphenethylamine/administration & dosage ; Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Protein Kinase Inhibitors/administration & dosage ; Stomach Neoplasms/pathology ; Treatment Outcome
مستخلص: 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.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: AGC kinases; AT13148; Anti-tumor activity and signaling; Gastric cancer
المشرفين على المادة: 0 (AT13148)
0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
0 (Pyrazoles)
7568-93-6 (2-Hydroxyphenethylamine)
EC 2.7.- (Protein Kinases)
تواريخ الأحداث: Date Created: 20160202 Date Completed: 20170523 Latest Revision: 20171127
رمز التحديث: 20231215
DOI: 10.1016/j.bbrc.2016.01.167
PMID: 26828267
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2104
DOI:10.1016/j.bbrc.2016.01.167