Inhibiting the Activity of ABCG2 by KU55933 in Colorectal Cancer

Abstract

Background: Therapeutic resistance is a frequent problem of cancer treatment and a leading cause of mortality in patients with metastatic colorectal cancer (CRC). Recent insight into the mechanisms that confer multidrug resistance has elucidated that the ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) assists cancer cells in escaping therapeutic stress caused by toxic chemotherapy. Therefore, it is necessary to develop ABCG2 inhibitors. Objective: In the present study, we investigated the inhibitory effect of KU55933 on ABCG2 in CRC. Methods: The cytotoxicity assay and drug accumulation assay were used to examine the inhibitory effect of KU55933 on ABCG2. The protein expressions were detected by Western blot assay. The docking assay was performed to predict the binding site and intermolecular interactions between KU55933 and ABCG2. Results: KU55933 was more potent than the known ABCG2 inhibitor fumitremorgin C to enhance the sensitivity of mitoxantrone and doxorubicin and the intracellular accumulation of mitoxantrone, doxorubicin and rhodamine 123 inside CRC cells with ABCG2 overexpression. Moreover, KU55933 did not affect the protein level of ABCG2. Furthermore, the docking data showed that KU55933 was tightly located in the drug-binding pocket of ABCG2. Conclusion: KU55933 can potently inhibit the activity of ABCG2 in CRC.

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells

“…The tritium-labeled drug accumulation assay ruled out this possibility as the drug resistant cells maintained minimum substrate accumulation even with high concentrations of Frontiers in Pharmacology frontiersin.org ceralasertib. In contrast, P-gp inhibitor verapamil and BCRP inhibitor Ko143 were able to increase substrate accumulation to a similar level as parental cells (Liu et al, 2022;Teng et al, 2024). Therefore, the results suggest that ceralasertib is unlikely to modulate the biological functions of P-gp and BCRP during short-term exposure.…”

The AKT inhibitor, MK-2206, attenuates ABCG2-mediated drug resistance in lung and colon cancer cells

“…Furthermore, both ABCB1 and ABCG2 transporters can decrease the efficacy of anticancer drugs that are structurally and mechanistically distinct, producing MDR ( Wei et al, 2020 ; Sucha et al, 2022 ). Although various inhibitors/modulators of the ABCB1 and ABCG2 transporters have been well characterized, none of these compounds have been approved for cancer, due to limited clinical benefits, toxic effects and problematic adverse drug-drug interactions ( Pena-Solorzano et al, 2017 ; De Vera et al, 2019 ; Dong et al, 2020 ; Kukal et al, 2021 ; Liu et al, 2022 ; Moinul et al, 2022 ). Recently, drug repurposing has emerged as a feasible strategy to overcome ABCB1- or ABCG2-mediated drug resistance in cancer ( Wang et al, 2020a ; Zhang et al, 2020 ; Wu et al, 2022 ).…”

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs

“…To overcome ABCG2-mediating MDR in cancer, we and other groups have identified some ABCG2 inhibitors, such as fumitremorgin C and its derivative ko143, elacridar, AG1478, sildenafil, AZ32, and KU55933, etc. [12][13][14][15][16][17][18]. However, it is still necessary to develop new ABCG2 inhibitors.…”