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INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France [S. A., C. R., S. R., M. B., C. L., T. A., J. M., C. G.]; Laboratory of Experimental Cancerology, University Hospital, B-9000 Gent, Belgium [S. V. B., E. B., M. M.]; Service de Médecine Interne Oncologie [C. L.], INSERM U402 [M. K.], Hôpital Saint-Antoine, 75020 Paris Cedex 20, France; and Service d’Oncologie, Hôpital Tenon, 75020 Paris Cedex 20, France [T. A.]
The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo. The c-kit receptor was identified as a Mr 145,000 immunoreactive band in human colon cancer cells HT29, HCT8/S11, and HCT116. Cellular invasion induced by 10 ng/ml stem cell factor (EC50 = 3 ng/ml) in HT29 cells was blocked by 1 µM STI571 (IC50 = 56 nM) and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol 3-kinase (LY294002), Rho GTPases (Clostridium botulinum exoenzyme C3 transferase), and Rho-kinase (Y27632). STI571 inhibited HT29 cell proliferation (IC50 = 6 µM) and induced apoptosis in vitro. These cellular effects were associated with a decrease in tumor growth. We also demonstrated that stem cell factor is a proangiogenic factor in vivo and in vitro. These encouraging results warrant further preclinical investigations and clinical trials on the use of the c-kit inhibitor STI571 as a chemotherapeutic agent in colon cancer prevention and in treatment of advanced colorectal cancers associated with liver metastases.
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