Becatecarin (rebeccamycin analog, NSC 655649) is a transport substrate and induces expression of the ATP-binding cassette transporter, ABCG2, in lung carcinoma cells

Purpose: ABCG2 overexpression has been linked to resistance to Topoisomerase inhibitors, leading us to examine the potential interaction between ABCG2 and becatecarin.

Methods: Interaction with ABCG2 was determined by ATPase assay, competition of [(125)I]iodoarylazidoprazosin (IAAP) photolabeling and flow cytometry. Cellular resistance was measured in 4-day cytotoxicity assays. ABCG2 expression was measured by fluorescent-substrate transport assays and immunoblot.

Results: Becatecarin competed [(125)I]-IAAP labeling of ABCG2, stimulated ATPase activity and, at concentrations greater than 10 microM, inhibited ABCG2-mediated transport. Becatecarin-selected A549 Bec150 lung carcinoma cells were 3.1-, 15-, 8-, and 6.8-fold resistant to becatecarin, mitoxantrone, SN-38 and topotecan, respectively. A549 Bec150 cells transported the ABCG2 substrates pheophorbide a, mitoxantrone and BODIPY-prazosin and displayed increased staining with the anti-ABCG2 antibody 5D3 compared to parental cells. Increased ABCG2 expression was confirmed by immunoblot.

Conclusions: Our results suggest that becatecarin is transported by ABCG2 and can induce ABCG2 expression in Cancer cells.