Mitoxantrone drug resistance

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Fig. 5 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. Fluorescent Compounds for the functional detection of multi drug resistance. Abbreviations CA-AM calcein AM, FL-3-AM fluo-3AM, Pot. Dyes potentiomeric dyes, RFI123 rhodaminel23, HST fioechst dye No. 33342, GS-N-PM N-Pyrenemaleimide glutathione conjugate, BOD-VER BODIPY verapamil, BOD-PRAS BODIPY prazosin, MX mitoxantrone, LYS LysoTracker dye. (Reproduced from [4])...

A specific inhibitor of BCRP is the tremorgenic mycotoxin fumitremorgin C (FTC). FTC blocked mitoxantrone transport by BCRP without affecting P-gp or MRPl-mediated drug resistance (Rabindran et al., 2000). However, due to neurotoxic effects in vivo apvplication is still not possible. 

Limtraknl, P. et al.. Modulation of the function of three ABC drug transporters, P-glycoprotein (ABCBl), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCCl) by tetrahydroenrenmin, a major metabolite of cur-enmin. Mol. Cell Biochem., 296, 85, 2007. 

Dixon, K. H., Horton, J., Kelley, K., Morrow, C., Cowan, K. H. (1992). Reduced intracellular drug accumulation in the absence of P-glycoprotein (mdrl) overexpression in mitoxantrone-resistant human MCF-7 breast cancer cells. Cancer Res. 52, 6175-6181. 

Ross, D. D., Schneider, E. (2000). Methotrexate cross-resistance in a mitoxantrone-seiected muitidrug-resistant MGF7 breast cancer ceii iine is attributabie to enhanced energy-dependent drug efflux. Cancer Res. 60, 3514-3521. 

Smitherman, P.K. and Townsend, A.J. (2006) Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Molecular Pharmacology, 69, 1499-1505. 

Doyle et al. first identified BGRP (breast cancer resistance protein) following exposure of breast cancer cells to an anticancer drug called mitoxantrone, a chemical relative of daunomycin and doxorubicin. This dimeric protein requires either homo- or Homo-dimerization for the protein to function as a membrane-bound pump. Once dimerized the protein can shuttle drug extracellularly from the membrane in a manner similar to that of the other ABC cassette proteins such as Pgp. 

Mitoxantrone (Novantrone) is supplied for intravenous infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose of 12 mg/m for 3 days as a component of a regimen that also includes cytosine arabinoside. Mitoxantrone also is used in advanced hormone-resistant prostate cancer in a dose of 12 to 14 mg/m every 21 days. Mitoxantrone has been approved by the FDA for the treatment of late-stage, secondary progressive multiple sclerosis. 

The characterization of a mitoxantrone-resistant breast cancer cell line that displayed an efflux-based MDR phenotype without expression of Pgp or MRPl led to the discovery of BCRP. This transporter, also known as mitoxantrone resistance protein (MXR) or placenta-specific ABC transporter (ABCP), is a half-transporter acting as a homo- or heterodimer to form an active transporter [22]. The substrate specificity of BCRP overlaps somewhat with that of Pgp and MRPl, suggesting a similar role in the pharmacokinetic of chemotherapeutic drugs. In fact, the overexpression of BCRP in tumor cells confers resistance to mitoxantrone, topotecan, SN38, flavopiridol, doxorubicin, bisantrene, etoposide, and methotrexate [16]. 

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