Betulinic acid enhances gefitinib-sensitivity of pancreatic cancer cells via inhibition of STAT3 activation / 中国肿瘤生物治疗杂志
Chinese Journal of Cancer Biotherapy
;
(6): 948-954, 2019.
Article
in Chinese
| WPRIM
| ID: wpr-793292
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:
Available
Index:
WPRIM (Western Pacific)
Type of study:
Diagnostic study
Language:
Chinese
Journal:
Chinese Journal of Cancer Biotherapy
Year:
2019
Type:
Article
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