| dc.description.abstract | Multidrug resistance refers to the simultaneous resistance to structurally and mechanistically unrelated cytotoxic drugs. Chronic administration of cytotoxic drugs to patients with metastatic breast cancer results in the development of multidrug resistance, thus rendering chemotherapy unsuccessful. One mechanism by which multidrug resistance is conferred is the decreased intracellular drug accumulation due to the upregulation of the ATP-binding cassette (ABC) transporters. Jadomycins are polyketide-derived natural products produced by the soil actinomycetes Streptomyces venezuelae, ISP 5230. Jadomycins exhibit anticancer, antibacterial and antifungal activities. Pilot work in our laboratory demonstrated that jadomycin B exhibited similar cytotoxic effects in drug-sensitive and drug-resistant cancer cells. We hypothesize that jadomycins are poor substrates of ABCB1, ABCC1 and ABCG2 efflux transporters, and consequently will exhibit higher intracellular accumulation, which results in improved cytotoxic efficacy over existing chemotherapeutics that are rapidly effluxed by ABC transporters. Using methyltetrazolium (MTT) cell viability assays, the cytotoxic efficacy of nine jadomycin analogues (DNV, L, B, SPhG, F, W, S, T and N) in drug-sensitive and drug-resistant MCF7 breast cancer cells was evaluated. Jadomycin B, L, S and T were found to be equally toxic to drug-sensitive and drug-resistant ABCB1, ABCC1 or ABCG2-overexpressing MCF7 breast cancer cells. The inhibition of ABCB1, ABCC1 or ABCG2 efflux transporters with verapamil, MK-571 or ko143, respectively, did not significantly augment the cytotoxic effects of jadomycin DNV, L, B and S in drug-resistant MCF7 cells, suggesting that these jadomycins are poor substrates of the targeted transporter. Furthermore, all nine jadomycin analogues did not increase the intracellular accumulation of ABCB1, ABCC1 or ABCG2 probe fluorescent substrates in HEK-293 cells, indicating that these jadomycins do not inhibit the efflux function of the transporters. We conclude that jadomycins B, L and S are effective agents in the eradication of resistant breast cancer cells grown in culture, and that the ability of specific jadomycins to retain cytotoxic efficacy in resistant cells stems from their limited interactions with ABCB1, ABCC1 or ABCG2 efflux transporters. | en_US |
