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.
Highlights
Colorectal cancer (CRC) is one of the most prevalent and lethal tumor types in both men and women worldwide [1]
These findings indicate that QC synergizes with 5-FU in CRC cells and sensitizes them to 5-FU in hypoxia
Since it has been reported that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activity is negatively regulated by Keap1 [32], we investigated whether Jun N-terminal kinase-1 (JNK1) affects the Keap1-dependent degradation of Nrf2 in QC-treated CRC cells
Summary
Colorectal cancer (CRC) is one of the most prevalent and lethal tumor types in both men and women worldwide [1]. CRC patients frequently present with advanced and metastatic disease [2]. Surgical resection of the primary tumor is the standard treatment for CRC [1], metastatic disease is generally considered to be untreatable. Patients are often administered a combination of cytotoxic chemotherapeutic agents, usually with targeted therapy [4]. Drugs commonly used for the treatment of CRC include 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and leucovorin [4]. Among these drugs, 5-FU, which exerts its anticancer effects through the inhibition of thymidylate incorporation of metabolites into synthetic enzymes and DNA and RNA, is the most widely used agent for the systemic treatment of CRC [5]. Multiple clinical trials have demonstrated that single or combination therapy based on 5-FU yields a survival benefit for CRC patients [8]
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