@article{APS6782,
author = {Wei-feng Mao and Min-hua Shao and Pin-ting Gao and Ji Ma and Hui-juan Li and Gai-ling Li and Bao-hui Han and Chong-gang Yuan},
title = {The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib},
journal = {Acta Pharmacologica Sinica},
volume = {33},
number = {10},
year = {2016},
keywords = {},
abstract = {Aim: To elucidate the roles of receptor tyrosine kinases RET and VEGFR2 and the RAF/MEK/ERK signaling cascade in cancer treatment with sorafenib.
Methods: The cell lines A549, HeLa, and HepG2 were tested. The enzyme activity was examined under cell-free conditions using 384-well microplate assays. Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay. Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system. Protein expression analysis was performed using Western blotting.
Results: Sorafenib potently suppressed the activities of cRAF, VEGFR2, and RET with IC50 values of 20.9, 4 and 0.4 nmol/L, respectively. Sorafenib inhibited cRAF, VEGFR2, and RET via non-ATP-competitive, ATP-competitive and mixed-type modes, respectively. In contrast, sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines. The IC50 values for inhibition of A549, HeLa, and HepG2 cells were 8572, 4163, and 8338 nmol/L, respectively. In the 3 cell lines, sorafenib suppressed the cell proliferation mainly by blocking the MEK/ERK downstream pathway at the posttranscriptional level, which in turn regulated related gene expression via a feed-back mechanism.
Conclusion: This study provides novel evidence that protein kinases RET and VEGFR2 play crucial roles in cancer treatment with sorafenib.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/6782}
}