Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Japan.
Oncol Rep. 2010 Jan;23(1):217-22.
Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future.
小细胞肺癌（SCLC）的特征是内分泌机制。干细胞因子（SCF）及其受体 c-kit 可以激活 Akt 和细胞外信号调节激酶（Erk）途径。甲磺酸伊马替尼（STI571）可以抑制 c-kit 酪氨酸激酶活性，但临床试验结果失败。我们研究了针对 SCLC 的 SCF/c-kit 靶向治疗的可能性。使用 c-kit 阳性 SCLC 细胞（H209 和 H69 细胞）和 SCF 作为内分泌机制的模型，通过 Western blot 分析评估了 SCF、LY294002、PD98059 或 STI571 对 Akt 和 Erk 的影响。通过 MTT 测定评估了顺铂、依托泊苷伊立替康和氨柔比星（AMR）与或不与 SCF、LY294002、PD98059 或 STI571 联合治疗的细胞生长抑制作用。在 H209 细胞中，SCF 激活 Akt 和 Erk，而 STI571 抑制了这种激活，但在 H69 细胞中则不然。LY294002 和 PD98059 分别抑制了 H209 细胞中 SCF 诱导的 Akt 和 Erk 激活。STI571 单独在 SCF 处理的细胞中不发挥生长抑制作用。在 H209 细胞中，SCF 降低了 AMR 的细胞毒性，但不影响其他药物的敏感性。在 H69 细胞中，SCF 不影响对任何药物的敏感性。LY294002 但不是 PD98059 分别恢复或增强了 SCF 处理的 H209 或未处理的 H69 细胞中 AMR 的敏感性。STI571 将 SCF 处理的 H209 细胞的 AMR 敏感性恢复到基础水平。如果 SCF/c-kit 在体内有助于 Akt 的激活，那么 STI571 和 AMR 的联合可能对 SCLC 有效。此外，使用 AKT 抑制剂和 AMR 的联合可能是未来有前途的治疗方法。
