Cyclosporin A Is a Broad-Spectrum Multidrug Resistance Modulator

Abstract

Purpose: Overexpression of the multidrug resistance proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) is associated with treatment failure in acute myeloid leukemia (AML) and other malignancies. The Pgp modulator cyclosporin A has shown clinical efficacy in AML, whereas its analogue PSC-833 has not. Cyclosporin A is known to also modulate MRP-1, and we hypothesized that broad-spectrum multidrug resistance modulation might contribute to its clinical efficacy.Experimental Design: We studied the effects of cyclosporin A and PSC-833 on in vitro drug retention and cytotoxicity in resistant cell lines overexpressing Pgp, MRP-1, and BCRP and on nuclear-cytoplasmic drug distribution and cytotoxicity in cells overexpressing LRP. Cellular drug content was assessed by flow cytometry and nuclearcytoplasmic drug distribution by confocal microscopy.Results: Cyclosporin A enhanced retention of the substrate drug mitoxantrone in cells overexpressing Pgp (HL60/VCR), MRP-1 (HL60/ADR), and BCRP (8226/MR20, HEK-293 482R) and increased cytotoxicity 6-, 4-, 4-, and 3-fold, respectively. Moreover, cyclosporin A enhanced nuclear distribution of doxorubicin in 8226/MR20 cells, which also express LRP, and increased doxorubicin cytotoxicity 12-fold without an effect on cellular doxorubicin content, consistent with expression of wild-type BCRP, which does not efflux doxorubicin. Cyclosporin A also enhanced nuclear doxorubicin distribution in a second cell line with LRP overexpression, HT1080/DR4. PSC-833 enhanced mitoxantrone retention and cytotoxicity in cells overexpressing Pgp, but had no effect in cells overexpressing MRP-1, BCRP, or LRP.Conclusions: Cyclosporin A modulates Pgp, MRP-1, BCRP, and LRP, and this broad-spectrum activity may contribute to its clinical efficacy.

Molecular evidence and functional expression of a novel drug efflux pump (ABCC2) in human corneal epithelium and rabbit cornea and its role in ocular drug efflux

“…[ 14 C]-erythromycin (specific activity 48.8 mCi/mmol), a proven substrate for MRP (Terashi et al, 2000) was purchased from PerkinElmer Life and Analytical Sciences (Boston, MA). [ 3 H]-cyclosporine-A (specific activity: 8 Ci/mol), also a known substrate for MRP (Qadir et al, 2005), [ 3 H]-mannitol (specific activity: 50 mCi/mmol) and [ 14 C]-inulin (specific activity: 10 mCi/mmol) -paracellular markers were purchased from Amersham Biosciences, Ltd. (Piscataway, NJ). Twelve well plastic culture plates were purchased from Midwest Scientific (St. Louis, MO).…”

Imatinib is a substrate for various multidrug resistance proteins

“…CsA is an inhibitor of PGP, MRP1, LRP, and is supposed to be inhibitor of other multidrug resistance proteins [24]. The lowest Rh123 retention was observed in imatinib-resistant K-562R-0.1 cell line.…”

Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia

“…The Pgp inhibitor PSC-833 (valspodar) did not show benefit, but cyclosporin A has shown benefit in clinical trials, 1 possibly because it modulates other MDR proteins, including MRP-1 and BCRP, in addition to Pgp. 7 An alternative approach is to utilize cytotoxic drugs that are not substrates for MDR proteins. Cytarabine, which is part of standard AML therapy, is not an MDR substrate, and we demonstrated here that amonafide L-malate is not efficiently transported by Pgp, MRP-1 For amonafide L-malate, RR differed from those of doxorubicin (P ¼ 0.02) and mitoxantrone (P ¼ 0.004) and RMF also differed from those of doxorubicin (P ¼ 0.01) and mitoxantrone (P ¼ 0.01).…”

“…Clinical benefit will suggest that MDR proteins are important due to their role as drug efflux pumps, and that PSC-833 may have failed as it targeted Pgp alone, while cyclosporin A is a broad-spectrum MDR modulator. 7 M Burcu 1 For N-acetyl amonafide, RR also differed from those of daunorubicin (P ¼ 0.004), doxorubicin (P ¼ 0.01), mitoxantrone (P ¼ 0.002), idarubicin (P ¼ 0.003) and etoposide (P ¼ 0.02) and RMFs also differed from those of mitoxantrone (P ¼ 0.007), idarubicin (P ¼ 0.004) and etoposide (P ¼ 0.01). BCRP, breast cancer resistance protein; RMFs, resistance modifying factors; RRs, resistance ratios.…”

“…In term fetus, neonate, or normal adult differentiated tissues OFA-iLRP expression was not detected on the cell surface. 6,7 In contrast, OFA/iLR is re-expressed on a broad range of malignancies including some hematological tumor entities. [8][9][10] By utilizing a mouse anti-OFA/iLR monoclonal antibody (Dr J Coggin, Mobile, Al, USA) we show that OFA/iLR is frequently expressed on the surface of malignant plasma cells of patients with MGUS, MM and plasma cell leukemia (Figures 1a and b).…”