Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571.
Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 microM). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1 - 5 microM of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1 - 10 microM) inhibition of tyrosine phosphorylation of c-Kit as well as in vitro kinase activity (at 5 microM) of c-Kit in response to STI 571. STI 571 inhibited cell motility, as assessed by time-lapsed video microscopy, within 6 h of STI 571 treatment (5 microM). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 microM) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S. A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presence of STI 571. These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit. The effectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC. Oncogene (2000) 19, 3521 - 3528
Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
W L
WL
Wang
M E
ME
Healy
M
M
Sattler
S
S
Verma
J
J
Lin
G
G
Maulik
C D
CD
Stiles
J D
JD
Griffin
B E
BE
Johnson
R
R
Salgia
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008533:Megakaryocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018715:Microscopy, Video; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D004121:Dimethyl Sulfoxide