Proteasome inhibitors synergize with tumor necrosis factor-related apoptosis-induced ligand to induce anaplastic thyroid carcinoma cell death

被引:48
作者
Conticello, Concetta
Adamo, Luana
Giuffrida, Raffaella
Vicari, Luisa
Zeuner, Ann
Eramo, Adriana
Anastasi, Gabriele
Memeo, Lorenzo
Giuffrida, Dario
Iannolo, Gioacchin
Gulisano, Massimo
De Maria, Ruggero
机构
[1] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy
[2] Mediterranean Inst Oncol, Dept Expt Oncol, I-95029 Catania, Italy
[3] Univ Catania, Dept Physiol Sci, I-95125 Catania, Italy
[4] IOM Ric, I-95029 Catania, Italy
关键词
D O I
10.1210/jc.2006-2157
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive types of cancer characterized by complete refractoriness to multimodal treatment approaches. Therapeutic strategies based on the simultaneous use of proteasome inhibitors and death receptor ligands have been shown to induce apoptosis in several tumor types but have not yet been explored in ATC. Objective and Methods: The aim of this study was to investigate the ability of the proteasome inhibitor Bortezomib to induce apoptosis in ATC cell lines. Bortezomib was used as a single agent or in combination with TNF-related apoptosis-induced ligand (TRAIL), a member of the TNF family that selectively induces tumor cell apoptosis. The molecular effects of Bortezomib were investigated by analyzing the expression of key regulators of cell cycle and apoptosis and the activation of different apoptotic pathways. Results: Bortezomib induced apoptosis in ATC cells at doses achieved in the clinical setting, differently from conventional chemotherapeutic agents. Simultaneous treatment with low doses of Bortezomib and TRAIL had a synergistic effect in inducing massive ATC cell apoptosis. Bortezomib increased the expression of cytotoxic TRAIL receptors, p21 (WAF/CIP1) and proapoptotic second mitochondria-derived activator of caspases/direct inhibitor of apoptosis binding protein with low pI, and reduced the expression of antiapoptotic mediators such as cellular Fas-associated death domain-like IL-1 beta converting enzyme inhibitory protein, Bcl-2, Bcl-XL, and inhibitor of apoptosis-1, thus resulting in cell death induction through the mitochondrial apoptotic pathway. Conclusions: The combination of proteasome inhibitors and TRAIL synergizes to induce the destruction of chemoresistant neoplastic thyrocytes and could represent a promising therapeutic strategy for the treatment of anaplastic thyroid carcinoma.
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页码:1938 / 1942
页数:5
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