Τίτλος:
Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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-κB degradation, which leads to inactivation of the transcriptional factor nuclear factor-κB (NF-κB). NF-κB 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-κB 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. Copyright © 2006 by The Endocrine Society.
Συγγραφείς:
Mitsiades, C.S.
McMillin, D.
Kotoula, V.
Poulaki, V.
McMullan, C.
Negri, J.
Fanourakis, G.
Tseleni-Balafouta, S.
Ain, K.B.
Mitsiades, N.
Περιοδικό:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
Εκδότης:
Japan Endocrine Society
Λέξεις-κλειδιά:
bortezomib; caspase; doxorubicin; immunoglobulin enhancer binding protein; proteasome inhibitor; protein bcl 2; protein c jun; protein p21; protein p53, anaplastic carcinoma; antineoplastic activity; apoptosis; article; cancer cell; cancer cell culture; cell cycle; controlled study; drug effect; drug inhibition; drug mechanism; drug potentiation; gene overexpression; histopathology; human; human cell; human tissue; IC 50; in vitro study; medullary carcinoma; priority journal; protein degradation; protein expression; protein phosphorylation; thyroid carcinoma
DOI:
10.1210/jc.2005-2472
