Back to Journals » OncoTargets and Therapy » Volume 12

Fenofibrate potentiates chemosensitivity to human breast cancer cells by modulating apoptosis via AKT/NF-κB pathway

Authors Sun J, Zheng Z, Chen Q, Pan Y, Quan M, Dai Y

Received 17 October 2018

Accepted for publication 21 December 2018

Published 23 January 2019 Volume 2019:12 Pages 773—783


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Dr Sanjeev Srivastava

Jianguo Sun,1,2,* Zhibao Zheng,1,* Qi Chen,2 Yin Pan,1 Mingming Quan,1 Yuechu Dai1

1Department of Surgical Oncology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China; 2Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Background: Cumulatively, evidences revealed that fenofibrate used in the therapy of hyperlipidemia and hypercholesterolemia has anti-cancer effect in multiple cancer types. However, its function and underlying mechanism of chemosensitization in breast cancer remain poorly understood.
Materials and methods: The cytotoxicity of fenofibrate and anti-cancer drugs in breast cancer cells was determined by MTT. Apoptosis and mitochondrial membrane potential were measured using flow cytometry. Caspases and PARP cleavage, the Bcl-2 family members’ protein expression, as well as the activation of AKT and NF-κB signaling pathways were evaluated using Western blot assay. Real-time PCR was used to determine the mRNA expression of Bcl-2 family members.
Results: Our data indicated that fenofibrate suppressed SKBR3 and MDA-MB-231 cell growth in a dose-dependent manner, in the same way as paclitaxel, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin. Subtoxic levels of fenofibrate significantly augmented paclitaxel, TRAIL, ABT-737, and doxorubicin-induced apoptosis in both these two cell lines. Fenofibrate-promoted chemosensitivity is predominantly mediated by caspase-9 and caspase-3 activation and mitochondrial outer membrane permeabilization. Meanwhile, chemosensitivity promoted by fenofibrate also increased the expression of Bax and Bok and decreased the expression of Mcl-1 and Bcl-xl. Mechanistically, fenofibrate effectively reduced the phosphorylation levels of AKT and NF-κB. In addition, imiquimod, an NF-κB activator, could reverse fenofibrate-induced susceptibility to ABT-737-triggered apoptosis.
Conclusion: The present study provided the evidence of the underlying mechanisms on chemosensitization of fenofibrate by inducing the apoptosis of breast cancer in an AKT/NF-κB-dependent manner and implicated the potential application of fenofibrate in potentiating chemosensitivity in breast cancer therapy.

Keywords: human breast cancer, fenofibrate, chemosensitization, AKT, NF-κB

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]