Effects of the Tyrosine Kinase Inhibitor Imatinib on Neuroendocrine Tumor Cell Growth

AIM: We investigated the effects of the tyrosine kinase inhibitor imatinib (Gleevec) on neuroendocrine tumor cells. METHODS: Neuroendocrine tumor cells were incubated without and with imatinib. The effects on growth were examined by methylthiazoletetrazolium (MTT) assay. The c-Kit expression in human endocrine tumor tissue and cell lines was determined by immunohistochemistry and Western blot analysis, respectively. Cytotoxicity assay was performed by fluorescence-activated cell sorting. The telomerase activity was determined using the telomeric repeat amplification protocol. RESULTS: 28% of the insulinomas, 100% of the gastrinomas, and 38% of the carcinoids expressed c-Kit. Imatinib at concentrations >5 microM inhibited cell proliferation and induced apoptosis in both c-Kit-positive and c-Kit-negative cell lines. The PI-3K inhibitor wortmannin did not enhance the effects of imatinib. Imatinib did not sensitize endocrine tumor cells to doxorubicin and 5-fluorouracil. Imatinib inhibited the telomerase activity. CONCLUSION: Imatinib inhibits neuroendocrine tumor cell growth independently of c-Kit by inhibition of other tyrosine kinases or through tyrosine kinase independent pathways.