Mitoxantrone resistance

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. 

Komatani H, Kotani H, Hara Y, Naka-gawa R, Matsumoto M, Arakawa H et al. Identification of breast cancer resistant protein/mitoxantrone resistance/pla-centa-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole stmcture. Cancer Res 2001 61(7) 2827-2832. 

Miyake K, Mickley L, Litman T, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells demonstration of homology to ABC transport genes. Cancer Res 1999 59(1) 8 13. 

Figure 13.8 Examples of differential abundances of nuclear proteins in mitoxantrone-resistant and susceptible cells measured by densitometry and MS (Fu, 2004). a Nucleophosmin, determined to be unchanged and used to correct for the ratio of cells in the mixture.

Table 13.1 Abundance changes in nuclear proteins from mitoxantrone-resistant MCF-7 cells (Fu and Fenselau, 2005).

Using the criteria that abimdances are altered by at least twofold, 12 proteins of interest were identified in the nucleus and 15 in the plasma membrane of mitoxantrone-resistant MCF-7 cells. These are listed in Tables 13.1 and 13.2. Experimental variation in Table 13.1 is based on isotope ratio determinations of peptides from at least three gels, each from three separate cultures, thus incorporating both biological variability and experimental uncertainty. Experimental variation in Table 13.2 is based on isotope ratios measured for multiple peptides for each protein, from three separate cultures. 

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. 

Miyake, K., Mickley, L., Litman, T., Zhan, Z., Robey, R., Cristensen, B., Brangi, M., Greenberger, L., Dean, M., Fojo, T., et al. (1999) Molecular cloning of CDNAs which are highly over expressed in mitoxantrone-resistant cells demonstration of homology to... 

BCRP (also known as ABCG2) is a half ABC transporter. It is sometimes known as mitoxantrone resistance protein (MXR) because of its elevated expression in many cancer cell lines selected with mitoxantrone [54]. BCRP was first identified in breast cancer, but it is also found in several normal tissues, including placenta, liver canaliculi, small intestine, colon, the bronchial epithelial layer in the lung, and endothelial cells [55]. Its level is also elevated in other cancer types. For instance, an analysis of 150 untreated tumors with immuno-histochemical technique demonstrated a high incidence of BCRP overexpression particularly in tumors of gastrointestinal origin [56]. Elevated BCRP level is consistently associated with the phenotype that includes strong resistance to mitoxantrone, moderate resistance to anthracyclines, and sensitivity to... 

Brangi M, Litman T, Ciotti M, Nishiyama K, Kohihagen G, Takimoto C, Robey R, Pommier Y, Fojo T, Bates SE. Camptothecin resistance role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronida-tion in MXR-expressing cells. Cancer Res 1999 59 5938-5946. 

Boonstra R, Timmer-Bosscha H, van Echten-Arends J, van der Kolk DM, van den Berg A, de Jong B, Tew KD, Poppema S, de Vries EGE. Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation. Brit J Cancer 2004 90 2411-2417. 

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]. 

BCRP (ABCG2) The breast cancer resistance protein (BCRP) transporter is also known as mitoxantrone resistance (MXR) protein (Miyake et al., 1999 Krishnamurthy and Schuetz, 2006). BCRP is expressed in plasma membrane of placental syncytiotrophoblasts of the chorionic villus (Mao, 2008 Robey et al., 2009), mammary glands, testis, canicular membrane of hepatocytes, cortical and proximal tubules in the kidney, villous tip of intestinal cells in the small intestine, hematopoietic stem cells, endothelial cells of venules and capillaries, and the luminal surface of the endothelial cells at the blood-brain barrier. The substrate specificity for BCRP overlaps broadly with P-gp therefore, the clinical DDI implications for BCRP are as yet not well defined. The current limited data suggest that BCRP may have an impact on chemoresistance in cancer (Noguchi et al., 2009). Rosuvastatin and topotecan have been reported to increase plasma AUC for antivirals and cyclosporins (Allen et al., 2002 Maliepaard et al., 2001, Table 4.8). 

---