The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

Abstract

Multidrug resistance caused by the overexpression of the ATP-binding cassette (ABC) proteins in cancer cells remains one of the most difficult challenges faced by drug developers and clinical scientists. The emergence of multidrug-resistant cancers has driven efforts from researchers to develop innovative strategies to improve therapeutic outcomes. Based on the drug repurposing approach, we discovered an additional action of TMP195, a potent and selective inhibitor of class IIa histone deacetylase. We reveal that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs. We demonstrate that TMP195 inhibits the drug transport function, but not the protein expression of ABCB1 and ABCG2. The interaction between TMP195 with these transporters was supported by the TMP195-stimulated ATPase activity of ABCB1 and ABCG2, and by in silico docking analysis of TMP195 binding to the substrate-binding pocket of these transporters. Furthermore, we did not find clear evidence of TMP195 resistance conferred by ABCB1 or ABCG2, suggesting that these transporters are unlikely to play a significant role in the development of resistance to TMP195 in cancer patients.3 of 23 an ABCG2-overexpressing MDR variant of H460 human lung cancer cells, to SN-38 and topotecan in a concentration-dependent manner (Table 3). We found that TMP195 reversed ABCG2-mediated resistance to mitoxantrone and topotecan to a comparable level as that of Ko143, an ABCG2 benchmark inhibitor, in S1-M1-80 and H460-MX20 cancer cells. In comparison, TMP195 was least effective in reversing ABCG2-mediated resistance to SN-38 in both ABCG2-overexpressing cancer cell lines.

Erdafitinib Antagonizes ABCB1-Mediated Multidrug Resistance in Cancer Cells

“…We found that erdafitinib could stimulate the function of ATPase of ABCB1. It should be noted that, although several ABCB1 inhibitors were identified as stimulators of ATPase of ABCB1, ABCB1 overexpression might not necessarily cause drug resistance to those inhibitors (15,45). Further study is needed to determine if erdafitinib is an ABCB1 competitive inhibitor.…”

“…Our result was in consistent with other reports. For example, several TKIs, including glesatinib, TMP195, ulixertinib, and olmutinib, could bind to the drug-binding sites of ABC transporters, including ABCB1 and ABCG2, to reverse MDR (13,15,45,46).…”

Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines

“…AutoDock Vina [53] was used as a docking software for docking of LY3023414 with the structures of the inward-open conformation of human ABCB1 (PDBID:6QEX) [54] and ABCG2 (PDBID:5NJ3) [55] as previously described [56]. MGLtools software package (Scripps Research Institute) was used to prepare the pdbqt files.…”

Bruton’s Tyrosine Kinase (BTK) Inhibitor RN486 Overcomes ABCB1-Mediated Multidrug Resistance in Cancer Cells

“…Furthermore, the cytotoxicity experiments excluded RN486 is a substrate of ABCB1. In addition, even though some ABCB1 inhibitors were identified as stimulators in ATPase assay of ABCB1, ABCB1 overexpression might not necessarily cause drug resistance to those inhibitors ( Cui et al, 2019a ; Wu et al, 2020 ). The reasons for unchanged ATPase activity with 0-10 μM RN486 may vary included additional interactions between RN486 with inhibitor binding site.…”