SU6656 is a small-molecule
indolinone that selectively inhibits
Src family kinase and induces death of
cancer cells. The aim of the present study was to investigate the influence of
SU6656 on cell survival and to assess the role of p21 and PI3K/Akt signaling in cell survival resulting from
SU6656 treatment in
anaplastic thyroid carcinoma (ATC) cells. When 8505C, CAL62, and FRO ATC cells were treated with
SU6656, the viability of 8505C and CAL62 ATC cells decreased only
after treatment with
SU6656 at a dosage of 100 μM for 72 h, while the viability of FRO ATC cells decreased
after treatment with
SU6656 in a concentration- and time-dependent manner. Cell viability was not changed by pretreatment with the broad-spectrum
caspase inhibitor
z-VAD-fmk. Phospho-Src
protein levels were reduced, and p21
protein levels were elevated. Phospho-ERK1/2
protein levels were multiplied without alteration of total ERK1/2, total Akt, and phospho-Akt
protein levels. Regarding FRO ATC cells, the decrement of cell viability, the increment of cleaved
PARP-1 protein levels, and the decrement of phospho-Src
protein levels were shown in p21
siRNA- or LY294002-pretreated cells compared to SU6656-treated control cells. ERK1/2
siRNA transfection did not affect cell viability and
protein levels of cleaved PARP-1, p21, and Akt. In conclusion, these results suggest that
SU6656 induces
caspase-independent death of FRO ATC cells by overcoming the resistance mechanism involving p21 and Akt. Suppression of p21 and Akt enhances the cytotoxic effect of
SU6656 in FRO ATC cells.