ZD6474 inhibits Src kinase leading to apoptosis of imatinib-resistant K562 cells.
ZD6474 is an orally available, small-molecule tyrosine kinase inhibitor. This study explores the effect of ZD6474 on imatinib-resistant K562 cell lines, which show markedly increased SRC family kinases (SFKs) activity. ZD6474 induces growth arrest and apoptosis of imatinib-resistant and parental K562 cells, as well as inhibition of Src activity and its downstream effectors, the anti-apoptotic Bcl-2 family. ZD6474 treatment also inhibits the activity of STAT3 and reactivation of its activity results in suppression of the anti-tumor effects of SFKs inhibitors. A single oral administration of ZD6474 produced dose-dependent inhibition of imatinib-resistant K562 cells xenograft tumors. These results suggest that clinical assessment of ZD6474 against imatinib-resistant CML is warranted.
Jia
Hong-Yun
HY
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China.
Wu
Jiang-Xue
JX
Zhu
Xiao-Feng
XF
Chen
Jie-Min
JM
Yang
Shi-Ping
SP
Yan
Hai-Jiao
HJ
Tan
Li
L
Zeng
Yi-Xin
YX
Huang
Wenlin
W
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020014:K562 Cells; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; D019061:src-Family Kinases; C452423:vandetanib