Reversal of breast cancer resistance protein–mediated drug resistance by tryprostatin A

Abstract

MDR in human cancers is one of the major causes of failure of chemotherapy. A member of the superfamily of ABC transporters, BCRP, was demonstrated to confer an atypical MDR phenotype to tumor cells. To overcome the BCRPmediated drug resistance, the fungal secondary metabolite TPS-A, a diketopiperazine, was analyzed with regard to its potency to reverse the BCRP-mediated drug-resistant phenotype. At concentrations of 10 -50 M, TPS-A reversed a mitoxantrone-resistant phenotype and inhibited the cellular BCRP-dependent mitoxantrone accumulation in the human gastric carcinoma cell line EPG85-257RNOV, the human breast cancer cell line MCF7/AdrVp (both exhibiting acquired BCRP-mediated MDR) and the BCRP cDNA-transfected breast cancer cell line MCF-7/BCRP clone 8. No cytotoxicity was seen at effective concentrations. 2 Clinical MDR of malignancies to many antineoplastic agents, the major obstacle in the successful treatment of cancer, may be in part due to increased activity of these broadspecificity plasma membrane-localized drug efflux pumps, like the most extensively studied MDR transporter P-gp. 3 The energydependent xenobiotic transport activity results in decreased intracellular concentrations of antitumor agents. P-gp-depending MDRs are often designated as classical MDR.A relatively new member of the ABC-transporter family is BCRP (MXR, ABCG2), 4 a 72 kDa ABC half-transporter consisting of 655 amino acid residues, which probably homodimerize to form an active transport complex. 5 BCRP is overexpressed in a variety of human MDR cancer cell lines, exhibiting an atypical MDR or a non-Pgp-mediated MDR phenotype. Elevated expression of BCRP results in resistance of various cancer cell lines to antitumor drugs, including mitoxantrone, topotecan, daunorubicin, doxorubicin and bisantrene. 6 Transfection experiments using the BCRP-encoding cDNA also transmit an atypical MDR phenotype to former drug-sensitive cancer cells. 7 High expression levels of BCRP were also detected in blast cells from patients with acute leukemia whose malignant disease was drug-resistant. 8,9 Moreover, BCRP has been identified and characterized as a novel stem cell transporter. 10 In a murine system, BCRP expression was highly conserved in primitive stem cells from a variety of sources, including hematopoietic and embryonic stem cells. The level of BCRP protein expression directly correlated with the stem cellcharacterizing side population phenotype.Different versions of BCRP-specific cDNAs have been isolated from drug-selected cell lines displaying distinctly different atypical MDR phenotypes. These versions exhibited polymorphisms at amino acid position 482, presumed to be at the start of the third transmembrane helix. Wild-type BCRP protein containing an alkaline arginine at position 482 is unable to transport the cationic dye rhodamine 123, whereas BCRP with a neutral glycine or threonine at this position is able to transport it. 11 These mutations confer differences in substrate specificity to anticancer drugs, including methotrexate. 12 ...

Human limbal epithelium contains side population cells expressing the ATP-binding cassette transporter ABCG2

“…Hoechst 33342 dye efflux activity was also inhibited by a novel ABCG2 inhibitor, TPS-A (Fig. 2B), that is known not to inhibit another important ATP-binding cassette transporter, P-glycoprotein [23]. These data strongly suggest that ABCG2 is a major contributor to the SP phenotype of limbal epithelial cells.…”

“…Though verapamil is generally used to identify the SP phenotype in the Hoechst 33342 dye exclusion assay, it is insufficient in specificity to demonstrate the contribution of ABCG2 to the SP phenotype of limbal epithelial cells. As ABCG2-specific inhibitors, fumitremorgin C [33], 5D3 monoclonal antibody [13,22], and TPS-A [23] are reported. Our SP analysis of limbal epithelial cells using 5D3 and TPS-A showed that both 5D3 and TPS-A effectively inhibit Hoechst 33342 dye efflux from these cells (Fig.…”

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

“…Other notable BCRP inhibitors include, among others, novobiocin (54), tamoxifen, and its derivatives TAG-11 and TAG-139 (56), reserpine (57), the pipecolinate derivatives VX-710 (Biricodar) (61), tryprostatin A (a A. fumigatus second metabolite) (62), and dietary flavonoids such as chrysin and biochanin A (63).…”

ABC transporters: circadian rhythms and sex-related differences

“…FTC, temel farmakoloji çalış-malarında oldukça sık kullanılmasına rağmen nörotoksik etkileri nedeniyle klinikte kullanılmamaktadır. FTC'nin yanı sıra Ko 143, triprostatin A (TPS-A) ve silimarin, hesperetin, kuersetin ve daidzein gibi flavonoidler, siklosporin A, elakridar ve tarikidarın da BCRP'yi inhibe ettiği yapılan çeşitli çalışmalarla gösterilmiştir (74)(75)(76)(77)(78).…”