STI571 sensitizes nasopharyngeal carcinoma cells to cisplatin: sustained activation of ERK with improved growth inhibition.
Previously, we demonstrated that c-kit and stem cell factors (SCF) commonly co-expressed in primary and metastatic nasopharyngeal carcinomas (NPC), and in HONE-1 NPC cells with tyrosine autophosphorylation of c-kit. These findings suggest that the SCF/c-kit signaling may contribute to pathogenesis of NPC. Therefore, the efficacy of STI571 treatment alone and when combined with cisplatin on HONE-1 cells were evaluated. STI571 induced growth inhibition at the IC50 concentration (14.9 microM). When the concentration was at or higher than 30 microM, the induction of cell apoptosis was observed. The effects of STI571 were shown to be mediated by the sustained activation of ERK but did not involve the inhibition of c-kit signal activity. When the STI571 (5 microM) and cisplatin (5 microg/ml) treatments were combined, there were further inductions of ERK activation resulting in obviously enhanced growth inhibition and induction of cell apoptosis. In a xenograft model, STI571 (50 mg/kg/day) showed only a limited ability to inhibit HONE-1 cell growth, but when combined with cisplatin (3 mg/kg/twice a week) treatment, there was a significant improvement in growth inhibition compared with STI571 or cisplatin treatment alone. Our results provide experimental support for the advanced NPC therapeutic trials using the combined STI571 and cisplatin treatment.
Sheu
Lai-Fa
LF
Department of Pathology, Tri-Service General Hospital, Taipei 114, Taiwan, ROC. laifakimo@yahoo.com.tw
Young
Zuei-How
ZH
Lee
Wen-Cheng
WC
Chen
Yu-Fang
YF
Kao
Woei-Yau
WY
Chen
Ann
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D002277:Carcinoma / Q000188:drug therapy*; D016923:Cell Death; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin