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Antitumor Effects of the Proteasome Inhibitor Bortezomib in Medullary and Anaplastic Thyroid Carcinoma Cells in Vitro

Department of Medical Oncology (C.S.M., D.M., C.M., J.N., G.F., N.M.), Dana Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115; Department of Pathology (V.K.), School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; Massachusetts Eye and Ear Infirmary (V.P.), Harvard Medical School, Boston, Massachusetts 02114; Department of Pathology (G.F., S.T.-B.), University of Athens, 11527 Athens, Greece; Thyroid Cancer Research Laboratory (K.B.A.), Veterans Affairs Medical Center, Lexington, Kentucky 40511; and Thyroid Oncology Program (K.B.A.), Division of Hematology/Oncology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky 40536

Address all correspondence and requests for reprints to: Constantine S. Mitsiades, M.D., Ph.D., Department of Medical Oncology, Dana Farber Cancer Institute, Mayer Building, Room M555, 44 Binney Street, Boston, Massachusetts 02115. E-mail: constantine_mitsiades{at}dfci.harvard.edu.

Context: The ubiquitin-proteasome pathway is a major pathway for degradation of intracellular proteins. Proteasome inhibitors constitute a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. The proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the Food and Drug Administration for the treatment of multiple myeloma and is being studied intensely in several other malignancies. Its mechanism of action is complex but appears to include the inhibition of inhibitory-B degradation, which leads to inactivation of the transcriptional factor nuclear factor-B (NF-B). NF-B has been implicated in the pathophysiology of the most aggressive forms of thyroid carcinoma, i.e. medullary and anaplastic.

Objective and Methods: We evaluated the effect of bortezomib on a panel of thyroid carcinoma cell lines, originating from papillary, follicular, anaplastic, and medullary carcinomas.

Results: Bortezomib induced apoptosis in medullary and anaplastic cell lines with IC₅₀ values well within the range of clinically achievable concentrations and much lower than respective IC₅₀ values for other solid malignancies. Bortezomib inhibited NF-B activity; increased p53, p21, and jun expression; and induced caspase-dependent apoptosis. Sensitivity of thyroid carcinoma cells to bortezomib was partially decreased by overexpression of Bcl-2 or treatment with IGF-I, whereas the combination of bortezomib with chemotherapy (doxorubicin) was synergistic.

Conclusions: These data provide both insights into the molecular mechanisms of antitumor activity of proteasome inhibitors and the rationale for future clinical trials of bortezomib, alone or in combination with conventional chemotherapy, to improve patient outcome in medullary and anaplastic thyroid carcinomas.

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