Betulinic acid enhances gefitinib-sensitivity of pancreatic cancer cells via inhibition of STAT3 activation
10.3872/j.issn.1007-385x.2019.09.003
- VernacularTitle:桦木酸通过抑制STAT3的活化提高胰腺癌细胞对吉非替尼的敏感性
- Author:
WU Haixia
1
;
MAIMAITI Aikebaier
2
;
WANG Shuai
2
;
ZHOU Keting
2
;
SHI Senlin
2
Author Information
1. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China；2. Department of Pharmacy, the First Hospital of Ningbo City
2. College of Pharmaceutical Science, Zhejiang Chinese Medical University
- Publication Type:Journal Article
- Keywords:
betulinic acid (BEA);
pancreatic cancer;
Panc-1 cell;
Miapaca-2 cell;
gefitinib;
sensitization effect;
signal transducer and activator of transcription 3 (STAT3)
- From:
Chinese Journal of Cancer Biotherapy
2019;26(9):948-954
- CountryChina
- Language:Chinese
-
Abstract:
Objective: To investigate the effects and the underlying mechanisms of betulinic acid (BEA) on sensitizing pancreatic cancer cell lines Panc-1 and Miapaca-2 to gefitinib. Methods: After the cell culture was completed, Panc-1 and Miapaca-2 cells were randomly divided into 4 groups: control group (without treatment), BEAgroup, gefitinib group and BEAcombined with gefitinib group, respectively.The sensitization effect of BEAon gefitinib-insensitive pancreatic cancer cells was detected by MTS assay. The treatment effects of combined treatment of gefitinib and BEA against Panc-1 and Miapaca-2 cells were evaluated by colony formation assay. Flow cytometry was used to examine the effect of BEAon apoptosis of Panc-1 cells while WB was applied to determine the effect of BEAonapoptosis-related proteins. Surface plasmon resonance (SPR) experiment was used to detect the direct combination between signal transducer and activator of transcription 3(STAT3) and BEA; Molecular docking and molecular dynamics simulation experiments were adopted topredict the combining mode between STAT3 and BEA. Results: BEA synergistically enhanced the gefitinib-sensitivity of pancreatic cancer Panc-1 and Miapaca-2 cells (P<0.05), and IC50 of gefitinib on two cells were reduced by over 50%. Compared with single treatment, the combined treatment of BEA and gefitinib promoted the apoptosis and up-regulated the expressions of apoptosis-relatedproteins (cleaved-PARP and Bax), but reduced the apoptosis-inhibitory protein Bcl-2 (all P<0.05 or P<0.01). Moreover, the inhibitory effect of BEA on STAT3 activation in Panc-1 cells was in a dose-dependent mannar (P<0.01). BEA stabilizes its binding to STAT3 by forming hydrogen bonds with Lys-591 and Ser-613 of STAT3; in the meanwhile, BEA stabilized inthebinding site of STAT3, there by blocking STAT3 dimerization to enhance the drug sensitivity. Conclusion: Combined use of BEA and gefitinib could significantly inhibit the proliferation and induce apoptosis of Panc-1 and Miapaca-2 cells, which might be mediated by the inhibition of BEA on STST3.
- Full text:20190903.pdf
