Ohshima Mitsuhiro, Yamaguchi Yoko, Kappert Kai, Micke Patrick, Otsuka Kichibee
Department of Biochemistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
Biochem Biophys Res Commun. 2009 Apr 3;381(2):165-70. doi: 10.1016/j.bbrc.2009.02.012. Epub 2009 Feb 10.
PDGF-B-transfected, sis-NIH3T3 fibroblasts serve as a model system for examining the role of PDGF signaling in tumors. We have found that imatinib/STI571, a tyrosine kinase inhibitor targeting PDGF receptors, induces apoptosis of sis-NIH3T3 fibroblasts cultured under serum free conditions, which was rescued by the addition of 10% newborn calf serum (NCS). Therefore, growth factors included in serum were tested with regard to their ability to rescue imatinib-induced apoptosis. While PDGF-AB, EGF, and IGF-I failed to protect imatinib-induced sis-NIH3T3 cell apoptosis, bFGF rescued it. The effects of bFGF were confirmed by both cell viability assays and Bax/Bcl-2 gene expression ratio. An FGF receptor inhibitor, PD166866, invalidated the protective effect of bFGF. However, combination of imatinib and PD166866 failed to induce cell death of sis-NIH3T3 cells when cultured in 10% NCS. These results indicate that synergistic administration of some types of tyrosine kinase inhibitors need to be tested under in vivo-like conditions to establish novel strategies in anti-cancer therapy.
血小板衍生生长因子B（PDGF - B）转染的、猿猴肉瘤病毒癌基因（sis）- NIH3T3成纤维细胞用作研究PDGF信号传导在肿瘤中作用的模型系统。我们发现，伊马替尼/STI571，一种靶向PDGF受体的酪氨酸激酶抑制剂，可诱导在无血清条件下培养的sis - NIH3T3成纤维细胞凋亡，而添加10%新生小牛血清（NCS）可挽救这种凋亡。因此，对血清中所含生长因子挽救伊马替尼诱导凋亡的能力进行了测试。虽然血小板衍生生长因子AB（PDGF - AB）、表皮生长因子（EGF）和胰岛素样生长因子I（IGF - I）未能保护伊马替尼诱导的sis - NIH3T3细胞凋亡，但碱性成纤维细胞生长因子（bFGF）可挽救这种凋亡。通过细胞活力测定和Bax/Bcl - 2基因表达比率均证实了bFGF的作用。一种成纤维细胞生长因子受体抑制剂PD166866使bFGF的保护作用失效。然而，当在10% NCS中培养时，伊马替尼和PD166866联合使用未能诱导sis - NIH3T3细胞死亡。这些结果表明，需要在类似体内的条件下测试某些类型酪氨酸激酶抑制剂的协同给药，以建立抗癌治疗的新策略。
