Abstract
ABCG2 is responsible for the multidrug resistance (MDR) phenotype, and strongly modulates cancer outcomes. Its high expression at a number of physiological barriers, including blood-brain and intestinal barriers, impacts on drug pharmacokinetics parameters. We characterized MBL-II-141, a specific and potent ABCG2 inhibitor. Combination of 10 mg/kg MBL-II-141 with the anticancer agent CPT-11 completely blocked the growth of 90% freshly implanted ABCG2-positive tumors. Moreover, the same combination slowed the growth of already established tumors. As required for preclinical development, we defined the main pharmacokinetics parameters of MBL-II-141 and its influence on the kinetics of CPT-11 and its active metabolite SN-38 in mice. MBL-II-141 distribution into the brain occurred at a low, but detectable, level. Interestingly, preliminary data suggested that MBL-II-141 is well tolerated (at 50 mg/kg) and absorbed upon force-feeding. MBL-II-141 induced a potent sensitization of ABCG2-positive xenografts to CPT-11 through in vivo ABCG2 inhibition. MBL-II-141 strongly increased CPT-11 levels in the brain, and therefore would be a valuable agent to improve drug distribution into the brain to efficiently treat aggressive gliomas. Safety and other pharmacological data strongly support the reglementary preclinical development of MBL-II-141.
Highlights
ATP-binding cassette (ABC) proteins secrete various endogenous and exogenous molecules to protect cells from xenobiotic- and toxin-induced alterations under physiological and pathological conditions
Following the onset of tumors growing from HEK293-ABCG2 cells or control HEK293-pcDNA3.1 cells, the animals were treated by CPT-11, either alone or in combination with MBLII-141
Our present study concerns the inhibitory effect of MBL-II-141 on ABCG2-mediated drug resistance to CPT-11
Summary
ATP-binding cassette (ABC) proteins secrete various endogenous and exogenous molecules to protect cells from xenobiotic- and toxin-induced alterations under physiological and pathological conditions. Three major ABC transporters, P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/MXR/ABCG2), are overexpressed and widely contribute to the multidrug resistance (MDR) phenotype. The latter is associated with a lower survival of cancer patients [1,2,3,4]. Anticancer therapy could eliminate the majority of tumor cells, generate clonal selection of aggressive tumor cells overexpressing ABCG2 and cause their relapse This suggests that the ABCG2 protein is an appealing therapeutic target, and inhibiting its mediated secretion or decreasing its expression level in cancer cells constitute potential strategies to overcome chemoresistance
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