Oncotarget

Research Papers:

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

Mylène Honorat _, Jérôme Guitton, Charlotte Gauthier, Charlotte Bouard, Florine Lecerf-Schmidt, Basile Peres, Raphaël Terreux, Héloïse Gervot, Catherine Rioufol, Ahcène Boumendjel, Alain Puisieux, Attilio Di Pietro and Léa Payen

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2014; 5:11957-11970. https://doi.org/10.18632/oncotarget.2566

Metrics: PDF 1898 views  |   HTML 2273 views  |   ?  


Abstract

Mylène Honorat1,2,3, Jérôme Guitton1,4,5, Charlotte Gauthier3, Charlotte Bouard2, Florine Lecerf-Schmidt6, Basile Peres6, Raphaël Terreux1,3, Héloïse Gervot2, Catherine Rioufol5, Ahcène Boumendjel6, Alain Puisieux2, Attilio Di Pietro3, Léa Payen1,2,5

1Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Lyon 1, Lyon 69373, France

2INSERM UMR-S1052, CNRS UMR 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL), LabEx DEVweCAN, Centre Léon Bérard, Lyon 69373, France

3Equipe labellisée Ligue 2014, BMSSI UMR 5086 CNRS-Université Lyon 1, IBCP, Lyon 69373, France

4EA 3738, Laboratoire de Ciblage Thérapeutique en Cancérologie, Centre Hospitalier Lyon-Sud, Pierre Bénite, France

5Hospices Civils of Lyon, Laboratoire de Biochimie de Lyon Sud (CBS), Lyon, France

6Univ. Grenoble Alpes/CNRS, DPM UMR 5063, F-38041 Grenoble, France

Correspondence to:

Léa Payen, e-mail: [email protected]

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2566