Abstract
Simple SummaryMultidrug resistance or chemoresistance is a phenomenon where cells exhibit resistance to drugs that are pharmacologically and structurally distinct. ABCG2, a member of ABC transporter superfamily has been widely reported to be a principal cause of MDR in various cancers via pumping out various antineoplastic drugs. VKNG-1, a phenyltetrazole analogue selectively inhibits the ABCG2 transporter and reverses resistance to standard anticancer drugs both in vitro and in vivo in ABCG2-overexpressing colon cancers. This study presents the importance of VKNG-1 as a modulator of the ABCG2 transporter. In cancer patients, a combination of VKNG-1 and ABCG2 substrate drugs could be a beneficial treatment option for cells with high ABCG2 expression.The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.
Highlights
Cancer is the second main cause of death worldwide [1,2] and according to the World Health Organization, 1,762,450 new cases and around 606,880 cancer deaths have been disclosed in the United States [3,4]
1 and 6 μM of VKNG-1 in both S1, S1-M1-80 (Figure 1A) and ABCG2-overexpressing transfected cells (Figure 1B) and 1 and 5 μM of VKNG-1 in SW620, SW620/AD300 (Figure 1C), HEK293/pcDNA3.1, HEK293/ABCC1 and HEK293/ABCC10 cells (Figure 1D) and 3 μM of gilteritinib were chosen for the reversal experiments (Figure 1F)
The reversal efficacy of VKNG-1 for the ABCG2 transporter was similar to a known ABCG2 inhibitor (FTC) [29] at 6 μM
Summary
Cancer is the second main cause of death worldwide [1,2] and according to the World Health Organization, 1,762,450 new cases and around 606,880 cancer deaths have been disclosed in the United States [3,4]. One of the leading causes of drug resistance is the overexpression of ABCG2 transporter in metastatic CRC, and drugs such as SN-38 and its prodrug, irinotecan, are known substrates for the ABCG2 transporter [15]. One of the reasons behind MDR is the high expression of ATP-binding cassette (ABC) transporters, which attenuate the effect of antineoplastic agents by actively extruding them from cancer cells [12,17]. These efflux pumps utilize ATP to alter the conformation of the ABC transporters to efflux endogenous and xenobiotic compounds from various cancer cells and are present in mammals and other microorganisms [18]. A strategy of ABCG2 inhibition could be employed to increase bioavailability of chemotherapy agents and overcome cancer cell resistance [22]
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