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The Selective Tyrosine Kinase Inhibitor, STI571, Inhibits Growth of Anaplastic Thyroid Cancer Cells

Departments of Molecular Medicine (A.P., A.O., H.N., N.M., S.Y.), Urology (S.T.), International Health and Radiation Research (V.S.), and Molecular Pathology (M.N.), and Division of Endothelial Cell Biology (S.K.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan; and Department of Breast and Thyroid Surgery, Kawasaki Medical School (J.K.), Kurashiki 701-0192, Japan

Address all correspondence and requests for reprints to: Akira Ohtsuru, M.D., Ph.D., Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: ohtsuru{at}net.nagasaki-u.ac.jp.

To establish a molecular targeting therapy for anaplastic thyroid carcinomas, we studied the effect of the specific tyrosine kinase inhibitor, STI571, on anaplastic thyroid cancer cell lines highly expressing c-ABL ARO (mutated p53) and FRO (undetectable p53). These lines showed marked inhibition of cell growth after treatment with STI571. In contrast, the growth of papillary thyroid cancer cell lines that harbor wild-type p53 and have low levels of c-ABL was not affected by STI571. Fluorescent-activated cell sorting analysis revealed that STI571 treatment increased the fraction of FRO and ARO cells in S and G₂/M phases, respectively, indicating induction of S and G₂/M transition arrest. These changes were accompanied by inhibition of c-ABL phosphorylation/activation and increased expression of p21^cip1 in FRO and p27^kip1 in both FRO and ARO cells. Treatment with STI571 also led to reduction of cyclin A, B1, and CDC2 levels. The growth of FRO cells implanted into immunocompromised mice was significantly inhibited by STI571. Taken together, these results suggest that selective suppression of c-ABL activity by STI571 may represent a potential anticancer strategy for p53-mutated undifferentiated thyroid carcinomas.

This work was supported in part by Scientific Grants-in-Aid 12470221 and 13671158 from the Ministry of Education, Science, Culture, and Sports of Japan.

Abbreviations: CDK, Cyclin-dependent kinase; CML, chronic myelogenous leukemia; Crk, CT10 chicken retrovirus protein; DMSO, dimethylsulfoxide; ERK, extracellular signal-regulated kinase; GST, glutathione-S-transferase; IC₅₀, 50% inhibitory concentration; JNK, c-Jun NH₂-terminal kinase; PDGFR, platelet-derived growth factor receptor; PKC, phosphokinase C; wt, wild type.

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