Effect of a novel tyrosine kinase inhibitor HHGV678 on growth inhibition of Bcr-Abl wild type and IM-resistant cell lines in vitro.
- Author:
Lin QIU
1
;
Xiao-Dan WANG
;
Bo-Hai YU
;
Ren-Zhang LU
;
Fang GE
;
Xiu-Li WANG
;
Li-Jun CHEN
;
Bing-Hong HAN
;
Zhao-Ming ZHAN
;
Bo-Long ZHANG
;
Jun MA
Author Information
1. Harbin Institute of Hematolgy & Oncology, Harbin 150010, Heilongjiang Province, China. qiulin@csco.org.com
- Publication Type:Journal Article
- MeSH:
Aminopyridines;
Apoptosis;
drug effects;
Benzamides;
Cell Line, Tumor;
Cell Proliferation;
drug effects;
Drug Resistance, Neoplasm;
drug effects;
Fusion Proteins, bcr-abl;
metabolism;
Humans;
Imatinib Mesylate;
Piperazines;
pharmacology;
Protein Kinase Inhibitors;
pharmacology;
Protein-Tyrosine Kinases;
antagonists & inhibitors;
Pyrimidines;
pharmacology
- From:
Journal of Experimental Hematology
2008;16(5):1039-1043
- CountryChina
- Language:Chinese
-
Abstract:
This study was aimed to compare HHGV678 with imatinib (IM) in growth inhibition of Bcr-Abl wild type and IM-resistant cell lines, investigate the possibility of replacing IM with HHGV678 in treatment of chronic myeloid leukemia (CML) and IM-resistant CML patients. Viability of two Bcr-Abl wild type cell lines (K562 and 32Dp210) and 16 IM-resistant cell lines (K562R and 15 Bcr-Abl point mutant cell lines) treated with HHGV678 and IM was analyzed by MTT. The apoptosis of those cells was identified by flow cytometry with Annexin V staining and DNA ladder analysis. Western blot was applied for detecting the expression of Bcr-Abl and phosphotyrosine protein levels. The results indicated that HHGV678 significantly inhibited the growth of two Bcr-Abl wild types and IM-resistant cell lines in dose-dependent manner except cell line of T315I point mutant. IC(50) results showed that the growth inhibition of HHGV678 was 15.5 and 28-fold higher than that of IM in K562, 32Dp210 and 1.4 to 124.3-fold higher than that of IM in 15 IM-resistant cell lines respectively. Compared with IM, HHGV678 more significantly inhibited phosphotyrosine kinase protein of the cells mentioned above at different concentrations. With most importance, HHGV678 of 10.0 micromol/L induced cell apoptosis of 40.06% and 33.32% in K562R and 32Dp210(T315I) cell lines, which were much higher than that of IM (19.77% and 10.68%). It is concluded that HHGV678 is more effective than IM in the growth inhibition of Bcr-Abl wild type cell lines and IM-resistant cell lines, especially in strongest IM-resistant cell lines. Further studies are needed to show whether HHGV678 may be a novel targeting drug in treatment of CML and IM-resistant CML patients.
