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Bcl-2 Overexpression in Thyroid Carcinoma Cells Increases Sensitivity to Bcl-2 Homology 3 Domain Inhibition

Department of Medical Oncology (C.S.M., P.H., D.W.M., C.M., J.N., J.E.D., N.M.), Dana-Farber Cancer Institute, and Massachusetts Eye and Ear Infirmary (V.P.), Harvard Medical School, Boston, Massachusetts 02114; and Department of Pathology (V.K.), School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece

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 Bcl-2 family of proteins regulates apoptosis in various models and may represent a promising therapeutic target in human malignancies.

Objective/Methods: We evaluated the sensitivity of thyroid carcinoma cell lines (two papillary, one follicular, two anaplastic, three medullary) in vitro to BH3I-1 and BH3I-2', two cell-permeable inhibitors of the Bcl-2 homology (BH)-3 domain-mediated interaction between proapoptotic and antiapoptotic Bcl-2 family members. The thyroid carcinoma cell line FRO was stably transfected with cDNA for Bcl-2 or constitutively active Akt and evaluated for sensitivity to BH3-domain inhibition.

Results: BH3-domain inhibition disrupted the mitochondrial membrane potential in thyroid carcinoma cells, induced caspase-dependent apoptosis, and potently sensitized them to sublethal concentrations of doxorubicin and the proteasome inhibitor bortezomib (Velcade). Overexpression of constitutively active Akt suppressed BH3I-1-induced cell death. Bcl-2-overexpressing FRO cells were more resistant to conventional chemotherapeutic agents (such as doxorubicin) but significantly more sensitive to BH3I-1 than control cells and were found to overexpress caspase-9, caspase-8, Bmf, Bok, and Bik transcripts and express less A1, BRaf, and FLIP transcripts.

Conclusions: Bcl-2 expression protects thyroid carcinomas against chemotherapy-induced apoptosis. Nevertheless, overexpression of Bcl-2 may result in "oncogene addiction" of the cancer cell, which can be exploited by using BH3-domain inhibitors alone or in combination with other agents, including conventional chemotherapeutics (such as doxorubicin) or novel targeted therapies (such as the proteasome inhibitor bortezomib), for the treatment of aggressive thyroid cancer, including the medullary and anaplastic types.