Abstract
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 [125I]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 [ 125I]-IAAP labeling of ABCG2, stimulated ATPase activity and, at concentrations greater than 10 μM, 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.
Original language | English (US) |
---|---|
Pages (from-to) | 575-583 |
Number of pages | 9 |
Journal | Cancer chemotherapy and pharmacology |
Volume | 64 |
Issue number | 3 |
DOIs | |
State | Published - Jul 2009 |
Keywords
- ABCG2
- Becatecarin
- Drug-resistance
- Rebecamycin derivative
- Topoisomerase inhibitor
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)