The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan.

Abstract

The breast cancer resistance protein ABCG2 confers cellular resistance to irinotecan (CPT-11) and its active metabolite SN-38. We utilised ABCG2-expressing xenografts as a model to evaluate the ability of a non-toxic ABCG2 inhibitor to increase intracellular drug accumulation. We assessed the activity of irinotecan in vivo in SCID mice: irinotecan completely inhibited the development of control pcDNA3.1 xenografts, whilst only delaying the growth of ABCG2-expressing xenografts. Addition of MBLI-87, an acridone derivative inhibitor, significantly increased the irinotecan effect against the growth of ABCG2-expressing xenografts. In vitro, MBLI-87 was as potent as GF120918 against ABCG2-mediated irinotecan efflux, and additionally was specific for ABCG2. A significant sensitisation to irinotecan was achieved despite the fact that doses remained well below the maximum tolerated dose (due to the rather limited solubility of MBLI-87). This suggested that MBLI-87 is an excellent candidate to prevent drug efflux by ABCG2, without altering plasma concentrations of irinotecan and SN-38 after IP (intra-peritoneal) injections. This could constitute a useful strategy to improve drug pharmacology, to facilitate drug penetration into normal tissue compartments protected by ABCG2, and potentially to reverse drug resistance in cancer cells.

• Authors: O Arnaud, A Boumendjel, A Gèze, M Honorat, E L Matera, J Guitton, W D Stein, S E Bates, P Falson, C Dumontet, A Di Pietro, L Payen
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 4 Pg. 640-8 (Mar 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21216589 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 9-oxo-9,10-dihydroacridine-4-carboxylic acid 3,4-dimethoxyphenethyl amide
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Acridines
• Acridones
• Antineoplastic Agents, Phytogenic
• Neoplasm Proteins
• acridone
• Irinotecan
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, metabolism)
• Acridines (pharmacology)
• Acridones (pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (metabolism, pharmacology)
• Breast Neoplasms (drug therapy)
• Camptothecin (analogs & derivatives, metabolism, pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Female
• HEK293 Cells
• Humans
• Irinotecan
• Mice
• Mice, SCID
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Neoplasm Transplantation
• Transplantation, Heterologous