The selective tyrosine kinase inhibitor, STI571, inhibits growth of anaplastic thyroid cancer cells.
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 G(2)/M phases, respectively, indicating induction of S and G(2)/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.
Podtcheko
Alexei
A
Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Ohtsuru
Akira
A
Tsuda
Satoshi
S
Namba
Hirouki
H
Saenko
Vladimir
V
Nakashima
Masahiro
M
Mitsutake
Norisato
N
Kanda
Shigeru
S
Kurebayashi
Junichi
J
Yamashita
Shunichi
S
D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D016213:Cyclins / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000032:analysis / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D001549:Benzamides; D016213:Cyclins; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; D018844:Cyclin-Dependent Kinases; D020929:Mitogen-Activated Protein Kinase Kinases