Format

Send to

Choose Destination
Int J Mol Sci. 2019 Sep 5;20(18). pii: E4366. doi: 10.3390/ijms20184366.

Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer.

Author information

1
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Korea. hagyeong315@inha.edu.
2
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Korea. cwkimbio@inha.ac.kr.
3
Department of Internal Medicine, College of Medicine, Inha University, Incheon 22212, Korea. ldh@inha.ac.kr.
4
Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Korea. jaeslee@inha.ac.kr.
5
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea. jaeslee@inha.ac.kr.
6
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea. nbstoet@inha.ac.kr.
7
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea. nbstoet@inha.ac.kr.
8
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Korea. park001@inha.ac.kr.
9
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea. park001@inha.ac.kr.

Abstract

5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun N-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation.

KEYWORDS:

5-flourouracil; Nrf2; colorectal cancer; hypoxia; quinacrine

PMID:
31491980
DOI:
10.3390/ijms20184366
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center