Effect of sunitinib on the proliferation and survival of FRTL-5 cells / 대한내과학회지
Korean Journal of Medicine
;
: 509-517, 2010.
Article
in Korean
| 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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pyrroles
/
Thyroid Gland
/
Protein-Tyrosine Kinases
/
Thyrotropin
/
Carcinoma, Renal Cell
/
Immunoblotting
/
Proteins
/
Cell Cycle
/
Apoptosis
/
Annexin A5
Limits:
Animals
/
Humans
Language:
Korean
Journal:
Korean Journal of Medicine
Year:
2010
Type:
Article
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