Development of anti-lung cancer drugs overcoming drug resistance mediated by new molecules a drug efflux pump, breast cancer resistance protein (BCRP), and topoisomerase-I inhibitor

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We have explored that breast cancer resistance protein (BCRP)/ABCG2 of a half ABC transporter is a relatively specific transporter for topoisomerase I inhibitors of anti-lung cancer drugs (Biochem Biophys Research Commun 280:1216-1223, 2001). In addition, we have reported that BCRP/ABCG2 interacted directly with drugs and then immediately exported them out of cells, by using plasma membrane vesicles ovemxpressing BCRP (BiochemBiophys Res Commun 288:827-832, 2001). These findings were the first reports in biochemical analyses of BCRP.Thereafter, to explore the clinical role of BCRP/ABCG2 in lung cancer, we did expression and functional analyses of BCRP in clinical specimens and culture cells of non-small cell lung cancer (NSCLC). The results were that the levels of BCRP mRNA expression in the cell lines were significantly correlated with the BCRP function and the sensitivity to SN-38 and topotecan of topoisomerase I inhibitors, and that some NSCLC tissues expressed sufficient levels of … More the BCRP mRNA to confer drug resistance in vitro (Clin Cancer Res 9:3052-3057, 2003).Based on the above findings, to develop new anticancer drugs overcoming BCRP-mediated drug resistance, we synthesized about thirty of new derivatives of SN-38. These derivatives were biochemically tested whether they overcame the resistance by using plasma membrane vesicles. Consequently, we demonstrated that low-polarity camptothecin derivatives were potent lead compounds to overcome the resistance, and provided a practical approach to discover new drugs (Int J Cancer 110:921-927, 2004). On the other hand, to reverse BCRP-mediated drug resistance, we examined the reversal effects of novobiocin, a coumermycin antibiotic, in BCRP-over expressing cancer cells. Novobiocin significantly increased intracellular topotecan accumulation by competitive inhibition of BCRP function (Int J Cancer 108:146-151,2004). The findings suggested that novobiocin effectively overcame BCRP-mediated drug resistance at clinically acceptable concentrations. Very interestingly, we demonstrated that gefitinib of a novel molecular target drug for lung cancer reversed BCRP-mediated drug resistance in cancer cells and that gefitinib was a substrate for BCRP (Cancer Res 65:1541-1546, 2005). However, we found that gefitinib itself was not tranported by BCRP, using plasma membrane vesicles expressing BCRP.FR901228 is a novel his tone deacetylase (HDAC) inhibitor and shows antitumor effects in various cancer cells. We demonstrated that FR901228 inhibited proliferation of small-cell lung cancer cells and drug-resistant sublines very effectively at very low concentrations (Int J Cancer 104:238-242, 2003). Thereafter, we suggested that FR901228 induced caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway (Mol Cancer Ther 3:1397-1402, 2004). Considering the possible contributions of BCL-2 and BCL-XL to multidug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary small-cell lung cancer. Less