Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study

Abstract

Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [3H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents.

Lipid–Saporin Nanoparticles for the Intracellular Delivery of Cytotoxic Protein to Overcome ABC Transporter-Mediated Multidrug Resistance In Vitro and In Vivo

“…Our results indicated that the ABCB1-overexpressing SW620/AD300 cells were greater than 80-fold resistant, as compared to the parental SW620 cells, whereas the ABCG2-overexpressing NCI-H460/MX20 cells were greater than 150-fold resistant, compared to the non-resistant parental NCI-H460 cells. As reported previously, the resistance fold (RF) was calculated by dividing the substrate drug IC50 values in the drug-resistant cells by the IC50 values in the parental cells [10,46,58]. The resistant profile of our cells was comparable to the previously published studies [12,59].…”

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

“…The modified MTT colorimetric assay was used to detect the sensitivity of cells to anticancer drugs in vitro as previously described [19, 22]. The cells were trypsinized and resuspended in a final concentration of 4 × 10 3 cells/well.…”

“…The vanadate-sensitive ATPase activity of ABCB1 and ABCG2 in crude membranes of High-five insect cells was measured in the presence of voruciclib (0 to 40 µM) by PREDEASY ATPase Kits with modified protocols, as previously described [22, 27]. …”

Role of Wnt/β‐Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

“…Progresses in combination chemotherapy such as FOLFOX, XELOX/CAPOX, FOLFIRI, and therapeutic antibodies against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) have been shown to increase survival time. However, the emergence of multidrug resistance (MDR), accounting for the poor tumor response to antineoplastic agents, has greatly limited the efficacy of chemotherapeutic drugs and finally results in therapy failure in CRC patients [2][3][4]. Due to primary or acquired resistance, many patients either respond poorly to the chemotherapy or respond well initially but experience later tumor relapse and disease progression.…”