Sunitinib Exerts Only Limited Effects on the Proliferation and Differentiation of Anaplastic Thyroid Cancer Cells

被引:25
作者
D'Agostino, Maria [1 ]
Voce, Pasquale [2 ]
Celano, Marilena [1 ]
Sponziello, Marialuisa [3 ]
Moretti, Sonia [2 ]
Maggisano, Valentina [1 ]
Verrienti, Antonella [3 ]
Durante, Cosimo [3 ]
Filetti, Sebastiano [3 ]
Puxeddu, Efisio [2 ]
Russo, Diego [1 ]
机构
[1] Univ Catanzaro Magna Graecia, Dept Pharmacobiol Sci, I-88100 Catanzaro, Italy
[2] Univ Perugia, Dept Internal Med, I-06100 Perugia, Italy
[3] Univ Roma La Sapienza, Dept Clin Sci, Rome, Italy
关键词
ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; SODIUM/IODIDE SYMPORTER; IN-VITRO; EXPRESSION; CARCINOMA; THERAPIES; TARGETS; DESIGN;
D O I
10.1089/thy.2011.0060
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Novel molecularly targeted drugs are undergoing preclinical and clinical testing to assess their efficacy against refractory thyroid carcinomas. The multikinase inhibitor Sunitinib has been shown to inhibit the kinase activity of the RET oncogene and reduce proliferation in differentiated thyroid cancer cells harboring the RET/PTC rearrangement. In this study, we evaluated its effects in human cell lines derived from differentiated (TPC-1) and anaplastic (8505C, CAL-62, and C643) thyroid cancers. Methods: The cells exposed to various concentrations of Sunitinib were examined for: (1) cell viability and presence of apoptosis, analyzed by cell counts, MTT assay, trypan blue exclusion assay, western blotting, and immunofluorescence; (2) expression of cyclin D1 and phosphorylated and nonphosphorylated extracellular signal-regulated kinase (ERK) and Akt proteins, analyzed by western blotting; and (3) transcription of genes encoding thyrocyte differentiation markers (thyroid-stimulating hormone receptor, sodium/iodide symporter, thyroglobulin, and thyroperoxidase) and proangiogenic factors (vascular endothelial growth factor A, platelet-derived growth factors A and B), measured by quantitative reverse transcriptase-polymerase chain reaction. Results: Exposure to nanomolar concentrations of Sunitinib significantly reduced cell viability in only TPC-1 cells, and this effect was paralleled by reduction of cyclin D1 levels. Western blotting revealed reduced phosphorylation of ERK and Akt after 3 and 6 hours of drug exposure. In contrast, the growth of 8505C, CAL-62, and C-643 cells was significantly reduced only by micromolar concentrations of Sunitinib, mainly due to induced necrotic rather than apoptotic death. In these cells, Sunitinib exerted a few significant effects on the transcription of angiogenic factors or thyrocyte differentiation markers. Conclusions: Sunitinib has little or no effect on the growth or differentiation of anaplastic thyroid cancer cells, thus suggesting that it is unlikely to be effective in the treatment of anaplastic thyroid cancer.
引用
收藏
页码:138 / 144
页数:7
相关论文
共 35 条
  • [1] Sodium-iodide symporter (NIS) gene expression in lymph-node metastases of papillary thyroid carcinomas
    Arturi, F
    Russo, D
    Giuffrida, D
    Schlumberger, M
    Filetti, S
    [J]. EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2000, 143 (05) : 623 - 627
  • [2] Phase II Study of Daily Sunitinib in FDG-PET-Positive, Iodine-Refractory Differentiated Thyroid Cancer and Metastatic Medullary Carcinoma of the Thyroid with Functional Imaging Correlation
    Carr, Laurie L.
    Mankoff, David A.
    Goulart, Bernardo H.
    Eaton, Keith D.
    Capell, Peter T.
    Kell, Elizabeth M.
    Bauman, Julie E.
    Martins, Renato G.
    [J]. CLINICAL CANCER RESEARCH, 2010, 16 (21) : 5260 - 5268
  • [3] Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo
    Celano, M.
    Schenone, S.
    Cosco, D.
    Navarra, M.
    Puxeddu, E.
    Racanicchi, L.
    Brullo, C.
    Varano, E.
    Alcaro, S.
    Ferretti, E.
    Botta, G.
    Filetti, S.
    Fresta, M.
    Botta, M.
    Russo, D.
    [J]. ENDOCRINE-RELATED CANCER, 2008, 15 (02) : 499 - 510
  • [4] Sunitinib: From rational design to clinical efficacy
    Chow, Laura Q. M.
    Eckhardt, S. Gail
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2007, 25 (07) : 884 - 896
  • [5] Phase 2 study of sunitinib in refractory thyroid cancer
    Cohen, E. E.
    Needles, B. M.
    Cullen, K. J.
    Wong, S. J.
    Wade, J. L., III
    Ivy, S. P.
    Villaflor, V. M.
    Seiwert, T. Y.
    Nichols, K.
    Vokes, E. E.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (15)
  • [6] Sustained clinical responses to tyrosine kinase inhibitor sunitinib thyroid carcinoma
    Dawson, Sarah-Jane
    Conus, Nelly Marmy
    Toner, Guy C.
    Raleigh, Jeanette M.
    Hicks, Rodney J.
    McArthur, Grant
    Rischin, Danny
    [J]. ANTI-CANCER DRUGS, 2008, 19 (05) : 547 - 552
  • [7] How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy
    Fagin, JA
    [J]. JOURNAL OF ENDOCRINOLOGY, 2004, 183 (02) : 249 - 256
  • [8] Sunitinib Inhibits MEK/ERK and SAPK/JNK Pathways and Increases Sodium/Iodide Symporter Expression in Papillary Thyroid Cancer
    Fenton, Mike S.
    Marion, Kenneth M.
    Salem, Andrew K.
    Hogen, Rachel
    Naeim, Faramarz
    Hershman, Jerome M.
    [J]. THYROID, 2010, 20 (09) : 965 - 974
  • [9] Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism
    Filetti, S
    Bidart, JM
    Arturi, F
    Caillou, B
    Russo, D
    Schlumberger, M
    [J]. EUROPEAN JOURNAL OF ENDOCRINOLOGY, 1999, 141 (05) : 443 - 457
  • [10] Prohibitin Is Overexpressed in Papillary Thyroid Carcinomas Bearing the BRAFV600E Mutation
    Franzoni, Alessandra
    Dima, Mariavittoria
    D'Agostino, Maria
    Puppin, Cinzia
    Fabbro, Dora
    Di Loreto, Carla
    Pandolfi, Maura
    Puxeddu, Efisio
    Moretti, Sonia
    Celano, Marilena
    Bruno, Rocco
    Filetti, Sebastiano
    Russo, Diego
    Damante, Giuseppe
    [J]. THYROID, 2009, 19 (03) : 247 - 255