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Open AccessArticle

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

1
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Korea
2
Department of Internal Medicine, College of Medicine, Inha University, Incheon 22212, Korea
3
Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Korea
4
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea
5
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(18), 4366; https://doi.org/10.3390/ijms20184366
Received: 17 July 2019 / Revised: 3 September 2019 / Accepted: 4 September 2019 / Published: 5 September 2019
(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)
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. View Full-Text
Keywords: quinacrine; 5-flourouracil; hypoxia; Nrf2; colorectal cancer quinacrine; 5-flourouracil; hypoxia; Nrf2; colorectal cancer
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MDPI and ACS Style

Kim, H.G.; Kim, C.W.; Lee, D.H.; Lee, J.-S.; Oh, E.-T.; Park, H.J. Quinacrine-Mediated Inhibition of Nrf2 Reverses Hypoxia-Induced 5-Fluorouracil Resistance in Colorectal Cancer. Int. J. Mol. Sci. 2019, 20, 4366.

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