Efficacy and mechanism of FW-04-806 against HER2-positive gastric cancer cell lines
10.3969/j.issn.1001-1978.2014.11.007
- VernacularTitle:FW-04-806对HER2阳性胃癌细胞的抗肿瘤活性及其机制研究
- Author:
Min ZHANG
;
Pinrong CAO
;
Qundan WU
;
Yingli KONG
;
Lihong CHEN
;
Yanmei LUO
;
Wei HUANG
;
Jianhua XU
;
Min YE
- Publication Type:Journal Article
- Keywords:
FW-04-806;
HER2-positive gastric canc-er;
cell cycle;
apoptosis;
proliferous inhibition;
synergy
- From:
Chinese Pharmacological Bulletin
2014;(11):1513-1520
- CountryChina
- Language:Chinese
-
Abstract:
Aim To investigate the efficacy and mech-anism of FW-04-806 against HER2-positive gastric cancer cell lines,and the combination effect of FW-04-806 with lapatinib. Methods MTT assay was used to assess cell proliferous inhibition of FW-04-806 . The in-hibitory effect of colony formation was tested by colony formation. The protein expression, apoptotic induction and cell cycle arrest were detected by flow cytometry. Co-immunoprecipitation was used to investigate protein-protein interactions. The expression change of proteins was showed by immunohistochemistry. Western blot was applied to reveal the protein expression of related pro-liferous and apoptotic signaling pathway. The tumor growth inhibition was evaluated in tumor xenograft model. Results FW-04-806 obviously inhibited cell proliferation and colony formation in HER2 positive gastric cancer cell lines NCI-N87, OE19, with IC50 of (24. 17 ± 0. 02 ) , ( 29. 61 ± 0. 03 ) μmol · L-1 , re-spectively;FW-04-806 induced G2-M arrest and apop-tosis in a dose-dependent manner;200 mg · kg-1 of FW-04-806 showed tumor growth inhibition of 48. 0%( P < 0. 01 ) . In addition, FW-04-806 dissociated Hsp90/CDC37 complex, followed by degradation of HER2 and Akt,inhibiting the phosporylation of HER2, Akt and ERK, and increasing expression of apoptotic proteins,such as cleaved caspase-3 and cleaved parp. Furthermore,the combination of FW-04-806 with lapa-tinib in vitro was synergistic in NCI-N87 , which en-hanced the inhibition of cell proliferation and increased apoptotic rates. Conclusions FW-04-806 shows po-tent efficacy against HER2-positive gastric cancer cell lines in vitro and in vivo;FW-04-806 is synergistic with lapatinib.
