Abstract
Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.
Highlights
Multidrug resistance (MDR) is a frequent phenomenon that drastically limits the treatment of cancer patients
We found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 was a potent inhibitor of ABCG2 and could sensitize ABCG2-overexpressing colorectal cancer cells to chemotherapeutic drugs mitoxantrone and doxorubicin by increasing their intracellular concentrations
A monoclonal S1-M1-80 cell line with stable knockout of ABCG2 was acquired by single-cell culture, and its protein levels of ABCG2 were undetectable by western blot (Figure 1B)
Summary
Multidrug resistance (MDR) is a frequent phenomenon that drastically limits the treatment of cancer patients. Unlike its two functional homologs ABCB1 (P-glycoprotein) and ABCC1. Due to the unique structural architecture of ABCG2, the substrate profiles of it overlap with and yet differ from that of ABCB1 and ABCC1, consisting of topoisomerase inhibitors (i.e., mitoxantrone, SN38, topotecan, and doxorubicin), antimetabolites (i.e., 5-fluorouracil, and trimetrexatte), tyrosine kinase inhibitors (i.e., gefitinib, dasatinib, erlotinib, and sorafenib), photosensitizers (i.e., pheophorbide A and protoporphyrin IX), and fluorescent dyes (i.e., rhodamine 123 and Hoechst 33342) [7]. Potent inhibitors of ABCG2 have been identified in recent years, including fumitremorgin C (FTC) and its derivative ko143 [8, 9]. It is still necessary to identify novel inhibitors of ABCG2
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