Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin.

Abstract

Breast cancer resistance protein (BCRP)/MXR/ABCG2 is a new member of the family of ATP-dependent drug efflux proteins. Whereas overexpression of another member of this family, P-glycoprotein, minimally affects the cytotoxicity of camptothecins (CPTs), overexpression of wild-type as well as certain mutant BCRPs confers resistance to CPT analogues that are used clinically, including topotecan and irinotecan. Relatively little is known regarding the effects of BCRP on other CPT analogues. We now report studies of 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC) using mammalian cells stably transfected with constructs expressing a variety of efflux proteins, including wild-type BCRP and a mutant BCRP that contains a threonine rather than an arginine at position 482 (R482T). The results indicate that overexpression of either P-glycoprotein, multidrug resistance protein type 1, or multidrug resistance protein type 2 has little effect on the cytotoxicity of 9-NC or 9-AC. By contrast, overexpression of either wild-type or R482T BCRP confers resistance to 9-AC, but not to 9-NC. Furthermore, overexpression of wild-type or mutant BCRP is associated with reduced intracellular accumulation of 9-AC, but not 9-NC. In addition, immunoblotting studies indicate that whereas increased BCRP expression is evident in cells selected for resistance to irinotecan, BCRP expression is not detectable in two different cell lines selected for resistance to 9-NC. Taken together, these findings suggest that wild-type as well as R482T BCRP mediates cellular efflux of 9-AC but not 9-NC. Furthermore, the results suggest that polar groups at the 9 or 10 position of the CPT A ring facilitate interaction with BCRP and have implications for the clinical development of new CPT analogues.

• Authors: Rajeev Rajendra, Murugesan K Gounder, Ahamed Saleem, Jan H M Schellens, Douglas D Ross, Susan E Bates, Patrick Sinko, Eric H Rubin
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 12 Pg. 3228-33 (Jun 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 12810652 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents, Phytogenic
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Recombinant Fusion Proteins
• 9-aminocamptothecin
• rubitecan
• Camptothecin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, physiology)
• Animals
• Antineoplastic Agents, Phytogenic (metabolism)
• Camptothecin (analogs & derivatives, metabolism)
• Cell Division (drug effects)
• Dogs
• Drug Resistance, Neoplasm (physiology)
• Humans
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, physiology)
• Recombinant Fusion Proteins (physiology)
• Selection, Genetic
• Transfection
• Tumor Cells, Cultured (drug effects, metabolism)