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Submitted on November 11, 2005
Accepted on July 7, 2006
Department of Medical Oncology, Dana Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston MA 02115, USA; Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54621, Greece; Massachusetts Eye and Ear Infirmary, Harvard Medical School, 234 Charles Street, Boston, MA 02114; Department of Pathology, University of Athens, Athens, Greece; Thyroid Cancer Research Laboratory, Veterans Affairs Medical Center, Lexington, KY 40511 and Thyroid Oncology Program, Division of Hematology/Oncology, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536
* To whom correspondence should be addressed. 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 anti-tumor agents with pre-clinical and clinical evidence of activity against hematologic malignancies and solid tumors. The proteasome inhibitor bortezomib (PS-341, VelcadeTM) has been approved by FDA 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 I
B degradation, which leads to inactivation of the transcriptional factor NF-B. NF-B has been implicated in the pathophysiology of the most aggressive forms of thyroid carcinoma, i.e. medullary and anaplastic.
Objective/ 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 IC50s 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 by 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 anti-tumor 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.
B •
apoptosis •
caspases •
gene expression profiling •
thyroid carcinoma
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