MBL-II-141, a chromone derivative, enhances irinotecan (CPT-11) anticancer efficiency in ABCG2-positive xenografts

// Mylene Honorat 1, 2, 3 , Jerome Guitton 1, 4, 5 , Charlotte Gauthier 3 , Charlotte Bouard 2 , Florine Lecerf-Schmidt 6 , Basile Peres 6 , Raphael Terreux 1, 3 , Heloise Gervot 2 , Catherine Rioufol 5 , Ahcene Boumendjel 6 , Alain Puisieux 2 , Attilio Di Pietro 3 , Lea Payen 1, 2, 5 1 Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Universite Lyon 1, Lyon 69373, France 2 INSERM UMR-S1052, CNRS UMR 5286, Universite Lyon 1, Centre de Recherche en Cancerologie de Lyon (CRCL), LabEx DEVweCAN, Centre Leon Berard, Lyon 69373, France 3 Equipe labellisee Ligue 2014, BMSSI UMR 5086 CNRS-Universite Lyon 1, IBCP, Lyon 69373, France 4 EA 3738, Laboratoire de Ciblage Therapeutique en Cancerologie, Centre Hospitalier Lyon-Sud, Pierre Benite, France 5 Hospices Civils of Lyon, Laboratoire de Biochimie de Lyon Sud (CBS), Lyon, France 6 Univ. Grenoble Alpes/CNRS, DPM UMR 5063, F-38041 Grenoble, France Correspondence to: Lea Payen, e-mail: lea.payen-gay@univ-lyon1.fr Keywords: ABCG2, MDR phenotype, Inhibitors, Chemosensitization Received: June 17, 2014      Accepted: October 02, 2014      Published: January 20, 2015 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.