Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells Mark E. Issa a , Steven R. Hall b , Stephanie N. Dupuis c , Cathy L. Graham a , David L. Jakeman a,c and Kerry B. Goralski a,b Multidrug resistance remains a major obstacle in the effective treatment of metastatic breast cancer. 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. We have previously demonstrated that jadomycins, polyketide-derived natural products produced by Streptomyces venezuelae ISP5230, inhibit the growth of the human breast ductal carcinoma cell lines T47D and MDA-MB-435. To expand our understanding of jadomycin pharmacology, the goal of the present study was to determine whether the function of ABC efflux transporters affects the anticancer activity of jadomycins to MCF7 breast cancer cells. Seven jadomycin analogs (DNV, B, L, SPhG, F, S, and T) effectively reduced the viability of MCF7 control and ABCB1-, ABCC1-, or ABCG2-overexpressing drug-resistant MCF7 breast cancer cells as measured by methyltetrazolium cell viability assays and lactate dehydrogenase cytotoxicity assays. The inhibition of ABCB1, ABCC1, or ABCG2 with verapamil, MK-571, or Ko-143, respectively, did not augment the cytotoxicity of jadomycins DNV, B, L, SPhG, F, S, or T in drug-resistant MCF7 cells. Furthermore, jadomycins B, L, SPhG, F, S, and T did not increase the intracellular accumulation of ABCB1, ABCC1, or ABCG2 fluorescent substrates in HEK-293 cells stably transfected with ABCB1, ABCC1, or ABCG2. We conclude that jadomycins B, L, SPhG, F, S, and T are effective agents in the eradication of MCF7 breast cancer cells grown in culture, and that their cytotoxicities are minimally affected by ABCB1, ABCC1, and ABCG2 efflux transporter function. Anti-Cancer Drugs 25:255–269  c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Anti-Cancer Drugs 2014, 25:255–269 Keywords: ABC transporter, breast cancer, chemotherapy, jadomycin, multidrug resistance a College of Pharmacy, Faculty of Health Professions, b Department of Pharmacology, Faculty of Medicine and c Department of Chemistry, Faculty of Sciences, Dalhousie University, Halifax, Nova Scotia, Canada Correspondence to Kerry B. Goralski, PhD, College of Pharmacy, Dalhousie University, 5968 College St, PO Box 15000, Halifax, Nova Scotia, Canada B3H 4R2 Tel: +1 902 494 2052; fax: +1 902 494 1396; e-mail: kerry.goralski@dal.ca Received 15 May 2013 Revised form accepted 4 October 2013 Introduction Breast cancer is the most commonly diagnosed form of malignancy in women [1], and it is estimated that 20–30% of breast cancers will eventually metasta- size [2,3]. To date, metastatic breast cancer (MBC) is considered an incurable disease [4–6]. Despite intense efforts, current therapeutic options for MBC remain limited because of the problem of multidrug resistance (MDR), which is defined as the simultaneous resistance to an array of structurally and mechanistically unrelated drugs [2]. MDR affects virtually all therapies available for MBC, especially chemotherapies that are used when adjuvant or targeted therapies are pathologically incom- patible [2,5]. Current first-line chemotherapeutics for MBC include anthracyclines, taxanes, and epothi- lones [5]. If these chemotherapeutics fail, capecitabine and gemcitabine are often chosen to continue the treatment of MBC [5,7]; however, if resistance ultimately develops in response to these agents, few or no treatment options remain for MBC patients [2]. The most frequently encountered mechanism of MDR is the decreased intracellular accumulation of cytotoxic drugs due to the upregulation of ATP-binding cassette (ABC) efflux transporters [6,8,9]. As a result of this, the coadministration of a chemotherapeutic regimen with small molecule inhibitors of ABC transporters has been tested clinically as a strategy to overcome MDR in breast cancers [10–12]; to date this approach has not improved the outcomes of chemotherapy [13]. Although small molecule ABC transporter inhibitors may have eventual applications in the treatment of MBC, critical refine- ments are needed for this to be realized [13]. One possible alternative strategy to combat the problem of MDR is to identify novel anticancer agents that function independently of the relevant ABC transporters. Jadomycins are polyketide-derived natural products se- creted by the soil bacteria Streptomyces venezuelae ISP5230 [14], demonstrated to exhibit antibacterial, antifungal, and anticancer activities [15–20]. Our group synthesized and purified a number of jadomycins, 18 of Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anti-cancerdrugs.com). Preclinical report 255 0959-4973  c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CAD.0000000000000043 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.