| Title | Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways |
| Authors | Chen, Zuhua Liu, Zhentao Huang, Wenwen Li, Zhongwu Zou, Jianling Wang, Jingyuan Lin, Xiaoting Li, Beifang Chen, Dongshao Hu, Yanting Ji, Jiafu Gao, Jing Shen, Lin |
| Affiliation | Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Fu Cheng Rd 52, Beijing 100142, Peoples R China. Peking Univ, Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing, Peoples R China. Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Surg, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing, Peoples R China. |
| Keywords | Gimatecan Patient-derived xenografts Gastric cancer MAPK pathway CAMPTOTHECIN ANALOG GIMATECAN ADVANCED SOLID TUMORS PHASE-II TRIAL HUMAN NEUROBLASTOMA ORAL GIMATECAN CELLS APOPTOSIS CHEMOTHERAPY COMBINATION IRINOTECAN |
| Issue Date | 2017 |
| Publisher | JOURNAL OF TRANSLATIONAL MEDICINE |
| Citation | JOURNAL OF TRANSLATIONAL MEDICINE. 2017, 15. |
| Abstract | Background: We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models. Methods: GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed. Results: Gimatecan inhibited the proliferation of GC cells in vitro in a dose-and time-dependent manner by inducing apoptosis, and gimatecan had greater inhibitory effects than irinotecan. In addition, both gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2). Conclusions: For the first time, we have shown that the antitumor activity of gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that gimatecan might be an alternative to irinotecan in the treatment of GC. |
| URI | http://hdl.handle.net/20.500.11897/500410 |
| ISSN | 1479-5876 |
| DOI | 10.1186/s12967-017-1360-z |
| Indexed | SCI(E) PubMed Medline |
| Appears in Collections: | 北京肿瘤医院 |
