Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Abstract

The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.

SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines

“…Next, we evaluated the effect of SIS3 on drug-induced apoptosis in drug-sensitive cancer cells and MDR cancer cells overexpressing ABCB1 or ABCG2. KB-3–1 and KB-V-1 cells were treated with colchicine in the presence or absence of SIS3 for 48 h, whereas S1 and S1-M1–80 cells were treated with topotecan in the presence or absence of SIS3 for 48 h, processed and analyzed as described previously [23, 65]. As shown in Fig.…”

“…Immunoblot detection and quantification of (A) human ABCB1 in drug-sensitive human KB-3–1 cells and ABCB1-overexpressing KB-V-1 cells, or (B) human ABCG2 in drug-sensitive H460 cells and ABCG2-overexpressing H460-MX20 cells treated with DMSO (vehicle control) or increasing concentrations (0.1 – 1.0 μM) of SIS3 for 72 h according to the method described previously [65]. α-Tubulin was used as an internal loading control.…”

“…As a result, we and others have applied the drug repositioning (or drug repurposing) approach to discover drugs with known pharmacological and toxicological properties in the treatment of MDR cancer [34, 38, 50, 64]. In recent years, many inhibitors of protein kinases and signaling molecules, especially inhibitors of the epidermal growth factor receptor (EGFR), have been shown to reverse MDR mediated by ABCB1 or ABCG2 in cancer cells [23, 26, 48, 49, 51, 65]. However, many of these inhibitors are both transport substrates and/or inhibitors of an ABC drug transporter [19].…”

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

“…The overexpression of ABCB1 and ABCG2 has been linked to the development of acquired drug resistance in numerous types of cancer, such as advanced non-small cell lung cancer [42], breast cancer [43], acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) [44][45][46], chronic myeloid leukemia (CML) [47], chronic lymphocytic leukemia (CLL) [48], and multiple myeloma (MM) [49][50][51][52][53][54][55]. Rather than developing synthetic inhibitors of ABCB1 and ABCG2, we and others have focused on the repositioning of molecularly targeted therapeutic agents to modulate the function and/or expression of ABCB1 and ABCG2, which is an alternative approach to resensitize multidrug-resistant cancer cells to conventional chemotherapeutic agents [11,17,20,34,[56][57][58][59][60][61]. As a potent and highly selective class IIa HDAC inhibitor [21], TMP195 was shown able to trigger a therapeutic immune response that alters the tumor microenvironment, inhibits the proliferation and metastasis of breast tumors, and enhances the efficacy of chemotherapeutic agents and checkpoint blockade immunotherapy through modulation of macrophage phenotype [22].…”

ILC2s: New Actors in Tumor Immunity

“…Despite the different therapeutic approaches, including the use of immune checkpoint inhibitors, limited clinical benefits have been observed in patients (43). In this context, the tumor microenvironment (TME) seems to play a key role in driving prostate cancer progression and chemoresistance (44, 45). Focusing on ILCs in prostate cancer patients, we have shown that ILC2 levels positively correlate with tumor stage and with M-MDSC frequency (31).…”