Abstract
Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness. Our review presents the following five major causes of irinotecan resistance in human CRC: (1) cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter, ABCG2; (2) cellular irinotecan resistance is also induced in association with a nuclear receptor, pregnane/steroid X receptor (PXR/SXR), which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38; (3) irinotecan-resistant cells possess either reduced DNA topoisomerase I (Top1) expression at both the mRNA and protein levels or Top1 missense mutations; (4) alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs; and (5) CRC stem cells are the most difficult targets to successfully treat CRC. In the clinical setting, CRC gradually develops resistance to initially effective irinotecan-based therapy. To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.
Highlights
Irinotecan was developed and approved in Japan in 1994 as the first camptothecin derivative anti-cancer drug[1]
Pregnane X receptor (PXR) enrichment induced by SN-38 treatment to CYP3A4 gene Basseville et al.[26] enhancer and promoter regions SN-38 induced CYP3A4/5 (6-13-fold) and UGT1A1 and MRP2 by 2-3-fold
Our extensive review of the literature reveals the following five major issues leading to irinotecan resistance in human colorectal cancer (CRC): (1) Cellular irinotecan resistance is induced mainly through the increased expressions of drug efflux transporters, ABCG2
Summary
Irinotecan (irinotecan hydrochloride hydrate) was developed and approved in Japan in 1994 as the first camptothecin derivative anti-cancer drug[1]. The contribution of irinotecan to treat a wide variety of advanced solid tumors was extensively reviewed in 2019[2]. The review article describes useful regimens of drug combinations, such as folinic acid, 5-fluorouracil (5-FU), and irinotecan (FOLFIRI) and folinic acid, 5FU, irinotecan, and oxiplatin (FOLFIRINOX), to treat metastatic or advanced solid cancers. SN-38 itself is a very active anti-cancer metabolite of irinotecan that undergoes glucuronide conjugation by a UDPglucuronosyltransferase, UGT1A1, for the detoxification pathway [Figure 1]. The mechanism of the anti-cancer activity of SN-38 is the stabilization of the DNA Top1-DNA cleavable complex in cancer cells, resulting in the arrest of DNA replication[2]
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