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Effect of sunitinib on the proliferation and survival of FRTL-5 cells / 대한내과학회지
Korean Journal of Medicine ; : 509-517, 2010.
Artigo em Coreano | WPRIM | ID: wpr-219496
ABSTRACT
BACKGROUND/

AIMS:

Hypothyroidism has been reported in 36~85% of patients treated with sunitinib for renal cell carcinoma or gastrointestinal stromal tumor. However, the mechanism behind this hypothyroidism is unclear. This study evaluated the effects of sunitinib, a multi-target tyrosine kinase inhibitor, on the survival and proliferation of thyrocytes using FRTL-5 rat thyroid cells.

METHODS:

We examined the effect of sunitinib on cell proliferation in the presence and absence of thyroid stimulating hormone (TSH) in a colorimetric assay. Effects on the cell cycle were evaluated by flow cytometry, and on apoptosis using an annexin V apoptosis assay kit and by immunoblotting for caspase-3. Immunoblotting was also used to evaluate changes in the levels of intracellular proteins associated with the G1-S phase of the cell cycle.

RESULTS:

Sunitinib suppressed the proliferation of FRTL-5 cells in a dose- and time-dependent manner. This suppressive effect was enhanced by the presence of TSH (1 mU/mL). Sunitinib was subsequently shown, in flow cytometric analyses, to arrest the cell cycle at the G1-S phase. Furthermore, it induced apoptosis at a high concentration (15 micrometer) by activating caspase-3. G1-S phase arrest was associated with the induction of p27(kip1) and p21(cip1), whose expression is suppressed by TSH under control conditions. Sunitinib also decreased intracellular levels of cyclin D1 and cyclin-dependent kinase 2 in FRTL-5 cells.

CONCLUSIONS:

Sunitinib induced apoptosis in and suppressed the proliferation of FRTL-5 cells. Its suppression of proliferation was further enhanced by the presence of TSH. Sunitinib arrested the cell cycle in the G1-S phase by inducing the expression of p27(kip1)/p21(cip1), which are suppressed by TSH under normal conditions. Collectively, these findings suggest that sunitinib may interfere with TSH signaling pathways in normal thyrocytes.
Assuntos

Texto completo: DisponíveL Índice: WPRIM (Pacífico Ocidental) Assunto principal: Pirróis / Glândula Tireoide / Proteínas Tirosina Quinases / Tireotropina / Carcinoma de Células Renais / Immunoblotting / Proteínas / Ciclo Celular / Apoptose / Anexina A5 Limite: Animais / Humanos Idioma: Coreano Revista: Korean Journal of Medicine Ano de publicação: 2010 Tipo de documento: Artigo

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Texto completo: DisponíveL Índice: WPRIM (Pacífico Ocidental) Assunto principal: Pirróis / Glândula Tireoide / Proteínas Tirosina Quinases / Tireotropina / Carcinoma de Células Renais / Immunoblotting / Proteínas / Ciclo Celular / Apoptose / Anexina A5 Limite: Animais / Humanos Idioma: Coreano Revista: Korean Journal of Medicine Ano de publicação: 2010 Tipo de documento: Artigo