Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

PloS One
Zhaoyun LiuZhiyong Yu

Abstract

Epidermal growth factor receptor (EGFR) is over-expressed in about 50% of Triple negative breast cancers (TNBCs), but EGFR inhibitors have not been effective in treating TNBC patients. Increasing evidence supports that autophagy was related to drug resistance at present. However, the role and the mechanism of autophagy to the treatment of TNBC remain unknown. In the current study, we investigated the effect of autophagy inhibitor to gefitinib (Ge) in TNBC cells in vitro and in nude mice vivo. Our study demonstrated that inhibition of autophagy by 3-Methyladenine or bafilomycin A1 improved Ge's sensitivity to MDA-MB-231 and MDA-MB-468 cells, as evidence from stronger inhibition of cell vitality and colony formation, higher level of G0/G1 arrest and DNA damage, and these effects were verified in nude mice vivo. Our data showed that the mitochondrial-dependent apoptosis pathway was activated in favor of promoting apoptosis in the therapy of Ge combined autophagy inhibitor, as the elevation of BAX/Bcl-2, Cytochrome C, and CASP3. These results demonstrated that targeting autophagy should be considered as an effective therapeutic strategy to enhance the sensitivity of EGFR inhibitors on TNBC.

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Citations

Dec 14, 2017·Essays in Biochemistry·Jane FraserNoor Gammoh
May 28, 2019·Bioscience Reports·Fukai WangZhiyong Yu
Oct 31, 2019·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·Ying ShiJingjing Ren
Nov 20, 2019·Medicinal Research Reviews·Tuhina KhanGiuseppe Campiani
Feb 14, 2018·International Journal of Oncology·Yanyan HanLianhong Li
Aug 14, 2020·International Journal of Molecular Sciences·Rittibet YapasertRatana Banjerdpongchai
Jul 29, 2017·Cancer Metastasis Reviews·Brittany HaynesMalathy P Shekhar
Dec 29, 2020·Frontiers in Oncology·Charlotte Nicole HillGareth I Owen
Mar 16, 2021·Frontiers in Oncology·Malina XiaoBassam Janji
Jul 24, 2021·Journal of Pharmacological Sciences·Milica KosicLjubica Harhaji-Trajkovic
Aug 21, 2019·Seminars in Cancer Biology·Chandan Kanta DasMahitosh Mandal
Jun 21, 2020·Anti-cancer Agents in Medicinal Chemistry·Milad AshrafizadehAmirhossein Sahebkar

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Methods Mentioned

BETA
xenografts
FACS
Protein Assay
xenograft
flow cytometry

Software Mentioned

GraphPad Prism
GraphPad
ModiFit

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