BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer

Cancer Chemotherapy and Pharmacology
Seiji NagashimaShigeru Kohno

Abstract

Breast cancer resistance protein (BCRP) confers resistance against topoisomerase I inhibitors in cancer cells. Very recently, we reported that gefitinib reverses BCRP-mediated drug resistance by direct inhibition. However, it remains undetermined how much BCRP contributes to the resistance to topoisomerase I inhibitors in non-small cell lung cancer (NSCLC). The present study was designed to examine whether BCRP levels in NSCLC cells are correlated with the resistance to topoisomerase I inhibitors and the reversal effect by gefitinib. BCRP levels and its function were evaluated by Western blotting and flowcytometry, respectively. Gefitinib-insensitive NSCLC cells expressed various levels of BCRP, which were closely correlated not only with the IC50 values of SN-38 (r=0.874, P<0.05) and those of topotecan (r=0.968, P<0.001), but also with the reversal effects of 1 microM gefitinib on SN-38 resistance (r=0.956, P<0.001) and topotecan resistance (r=0.977, P=0.0001). BCRP levels accounted for between 80 and 90% of the variation in the resistance to topoisomerase I inhibitors and the reversal effects by gefitinib. Also, gefitinib increased intracellular topotecan accumulation in proportion to the BCRP levels. These findings suggest t...Continue Reading

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Citations

Jun 6, 2009·Cancer Chemotherapy and Pharmacology·Amalia AzzaritiAngelo Paradiso
May 13, 2010·Cancer Research·Angel M CarcabosoClinton F Stewart
Jun 6, 2013·Future Medicinal Chemistry·Florine Lecerf-SchmidtAhcène Boumendjel
Oct 22, 2010·Investigational New Drugs·Nienke A de VriesOlaf van Tellingen
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Oct 22, 2019·Future Medicinal Chemistry·Tiantian ZhangChanghu Xue
Jan 12, 2021·Frontiers in Cell and Developmental Biology·Zi-Ning LeiZhe-Sheng Chen
Aug 6, 2021·Developmental Cell·Marica Rosaria IppolitoStefano Santaguida

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