Effect of sulindac derivative K-80003 in combination with MEK inhibitor cobimetinib in breast cancer cells
10.3969/j.issn.1001-1978.2019.02.021
- Author:
Zong-Xi LI
1
Author Information
1. School of Pharmaceutical Sciences, Xiamen University
- Publication Type:Journal Article
- Keywords:
Breast cancer;
Cobimetinib;
Combination therapy;
P-ERK;
Signaling pathway;
Sulindac derivative
- From:
Chinese Pharmacological Bulletin
2019;35(2):251-254
- CountryChina
- Language:Chinese
-
Abstract:
Aim: To determine whether the inhibition of K-80003-activated p-ERK could potentiate the anticancer effect of K-80003 in vitro and in vivo. Methods: The effects of K-80003 in combination with the MEK inhibitor cobimetinib on ERK activation and tumor cell apoptosis in breast cancer cells were detected by Western blot and immunohistochemical staining in MCF-7 breast cancer cells and MMTV-PyMT mammary transgenic mice. Results: K-80003 activation of ERK in MCF-7 breast cancer cells and in MMTV-PyMT mammary transgenic mice was strongly inhibited by co-treatment with cobimetinib. The co-treatment also resulted in a strong induction of apoptosis and inhibition of the growth of tumor cells in vitro and in animals, as compared with K-80003 alone. It was detected that K-80003 in combination with cobimetinib synergistically inhibited the growth of MMTV-PyMT tumor strongly, suggesting that K-80003 activation of ERK serves as an escape mechanism by which tumor cells develop resistance to K-80003 treatment. Conclusion: An attractive approach is identified to enhance the therapeutic effect of K-80003 and to overcome potential resistance associated with the K-80003 therapy.
