Combination of everolimus and MK-2206 for synergistic inhibition of hepatocarcinoma cell proliferation
10.3867/j.issn.1000-3002.2017.08.003
- VernacularTitle:依维莫司和MK-2206联合用药协同抑制肝癌细胞增殖
- Author:
Zhen-Yu QIAO
1
;
Jian WANG
;
Xiao-Ye LYU
;
Fang HUANG
;
Peng WANG
;
Shan-Hu LI
;
Min HAN
Author Information
1. 贵州医科大学附属医院肝胆外科
- Keywords:
liver neoplasms;
sirolimus;
everolimus;
MK2206;
combination therapy;
drug resistance;
neoplasm
- From:
Chinese Journal of Pharmacology and Toxicology
2017;31(8):793-799
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To examine the synergistic inhibiory effect of combination of mammalian target of sirolimus (Rapamycin) (mTOR) inhibitor everolimus and AKT inhibitor MK-2206 on hepatocar-cinoma cell proliferation. METHODS HepG2 and BEL-7402 cells were treated with sirolimus and evero-limus alone for 0, 1, 3, 6, 12 and 24 h or in combination with insulin-like growth factor 1 receptor (IGF-1R) inhibitor NVP-AEW541 or AKT inhibitor MK2206 for 24 h. p70S6K and AKT kinase activityies were detected by Western blotting. Plate clone formation assay and CCK8 assay were used to detect the growth and proliferation of hepatocarcinoma cells treated with everolimus and MK2206 alone or in combi-nation. RESULTS Sirolimus and everolimus inhibited p70S6K activity while causing feedback activa-tion of AKT kinase activity at different time points (P<0.01). NVP-AEW541 and MK-2206 could inhibit AKT kinase feedback activation by everolimus (P<0.05). Colony formation of hepatocarcinoma cells treated with everolimus and MK-2206 in combination was significantly inhibited compared with everolimus or MK-2206 alone (P<0.01). Everolimus and MK-2206 in combination inhibited the proliferation rate of two types of hepatocarcinoma cancer cells by more than 45％ compared with everolimus used alone (P<0.01). CONCLUSION The resistance of sirolimus and its derivatives in hepatocellular carcinoma cells may be achieved throngh the feedback-activated PI3K/AKT pathway, and the combination therapy can synergistically inhibit the growth and proliferation of hepatocarcinoma cells.
