Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor.
Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.
Ueda
Yasuto
Y
Division of Medical Oncology and Molecular Respirology, Tottori University, Yonago 683-8504, Japan.
Igishi
Tadashi
T
Hashimoto
Kiyoshi
K
Suyama
Hisashi
H
Araki
Kunio
K
Sumikawa
Takashi
T
Takeda
Kenichi
K
Nakazaki
Hirofumi
H
Matsunami
Keiji
K
Kodani
Masahiro
M
Shigeoka
Yasushi
Y
Matsumoto
Shingo
S
Shimizu
Eiji
E
D018943:Anthracyclines / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
D018943:Anthracyclines; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; C055866:amrubicin; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt