Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells

Abstract

Abstract. 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. IntroductionSmall cell lung cancer (SCLC) is a highly aggressive neoplasm characterized by a high growth fraction, short doubling time and high rate of metastasis (1), but is sensitive to chemotherapy (2). Systemic chemotherapy prolongs the survival of SCLC patients (3), and cisplatin (CDDP), etoposide (VP-16), topoisomerase I inhibitors [irinotecan (CPT-11) and topotecan] (4,5) and amrubicin (AMR) (6) (a totally synthetic 9-aminoanthracycline) are used in regular clinical practice in Japan. Among these chemotherapeutic agents, the combination chemotherapy of CDDP and VP-16 is considered the standard first line chemotherapeutic regimen worldwide (7). Despite high response rates with these first line CDDP-based chemotherapies, most patients eventually experience disease progression. Accordingly, novel chemotherapeutic regimens based on new conceptions are needed for treating SCLC patients.SCLC is, per se, characterized by several autocrine growth mechanisms including stem cell factor (SCF) and its receptor c-kit, and c-kit overexpression is found in up to 70% of SCLC (8). In view of c-kit signal transduction, an SCF/c-kit can activate several intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/Erk) pathways (9).Imatinib mesylate (STI571) was developed as a Bcr-Abl inhibitor and has become a standard therapeutic drug for chronic my...