Abstract | 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:
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Authors | Constantine S Mitsiades, Patrick Hayden, Vassiliki Kotoula, Douglas W McMillin, Ciaran McMullan, Joseph Negri, Jake E Delmore, Vassiliki Poulaki, Nicholas Mitsiades |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 92
Issue 12
Pg. 4845-52
(Dec 2007)
ISSN: 0021-972X [Print] United States |
PMID | 17848408
(Publication Type: Journal Article)
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Chemical References |
- Antibiotics, Antineoplastic
- Antineoplastic Agents
- BH3 Interacting Domain Death Agonist Protein
- Boronic Acids
- Protease Inhibitors
- Pyrazines
- RNA, Neoplasm
- Tetrazolium Salts
- Thiazoles
- Bortezomib
- Doxorubicin
- Oncogene Protein v-akt
- thiazolyl blue
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Topics |
- Antibiotics, Antineoplastic
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- BH3 Interacting Domain Death Agonist Protein
(genetics)
- Blotting, Western
- Boronic Acids
(pharmacology)
- Bortezomib
- Carcinoma
(genetics)
- Carcinoma, Medullary
(genetics)
- Cell Line, Tumor
- Colorimetry
- Doxorubicin
(pharmacology)
- Genes, bcl-2
(genetics)
- Humans
- Membrane Potentials
(physiology)
- Oncogene Protein v-akt
(genetics)
- Protease Inhibitors
(pharmacology)
- Pyrazines
(pharmacology)
- RNA, Neoplasm
(biosynthesis, genetics)
- Tetrazolium Salts
- Thiazoles
- Thyroid Neoplasms
(genetics)
- Transcription, Genetic
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