Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia

Abstract

The multidrug resistance proteins (MRPs) MRP1, MRP2, MRP3, MRP5 and P-glycoprotein (P-gp) act in concert with each other to give a net resultant pump function in acute myeloid leukemia (AML). The aim of the present study was to analyze the activity of these proteins, which might be upregulated at relapse as compared with de novo AML due to clonal selection. The mRNA expression and activity of P-gp and the MRPs were determined with RT-PCR and flow cytometry, in conjunction with phenotype, as measured with the monoclonal antibodies CD34, CD38 and CD33, in 30 paired samples of de novo and relapsed AML. P-gp and MRP activity varied strongly between the cases (rhodamine 123 efflux-blocking by PSC833: 5.4 ؎ 7.7, and carboxyfluorescein efflux-blocking by MK-571: 4.3 ؎ 6.7, n ‫؍‬ 60). P-gp and MRP activity were increased in 23% and 40% of the relapse samples, and decreased in 30% and 20% of the relapse samples, respectively (as defined by a difference of Ͼ2 ؋ standard deviation of the assays). Up-or downregulation of mRNA expression was observed for MDR1 (40%), MRP1 (20%), MRP2 (15%), MRP3 (30%), and MRP5 (5%). Phenotyping demonstrated a more mature phenotype in 23% of the relapsed AML cases, and a more immature phenotype in 23% of the relapses, which was independent of the karyotypic changes that were observed in 50% of the studied cases. P-gp and MRP activity correlated with the phenotypic changes, with higher P-gp and MRP activities in less mature cells (r ‫؍‬ −0.66, P Ͻ 0.001 and r ‫؍‬ ؊0.31, P ‫؍‬ 0.02, n ‫؍‬ 58). In conclusion, this study shows that P-gp and MRP activity are not consistently upregulated in relapsed AML. However, P-gp and MRP activities were correlated with the maturation stage as defined by immune phenotype, which was observed to be different in 46% of the relapses. Leukemia (2001) 15, 1544-1553.

MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

“…It is possible that the different results are due to the different methods used. We have (24,47). MRP2 is expressed in normal lymphocytes (48), and even <10% of lymphocytes could increase the level of MRP2 in the blast samples (49).…”

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

“…Some of them, such as nonsmall-cell lung cancer (NSCLC) [13,109,150,175] or chronic lymphoblastic leukemia [63,111], generally exhibit high level of MRP1 expression and these tumors are intrinsically multidrug resistant, whereas others such as small-cell lung cancer (SCLC) [175], gastric carcinoma [2,34], neuroblastoma [114], and retinoblastoma [21] exhibit high MRP1 expression with a lower frequency. A correlation between the MRP1 expression and the stage of the tumor has been reported in certain tumor types, such as acute myeloblastic leukemia (AML) [165], myelodysplastic syndromes (MDS) [124], and prostate cancer [153]. On the other hand, in lung adenocarcinomas, a reverse correlation was seen with tumor grading [13].…”

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

“…Moreover, another potential weakness of rapamycin is represented by the fact that this drug could be exported from cells through ATP-binding cassette (ABC) type transporters that mediate multidrug resistance such as 170-kDa P-glycoprotein, 217 and AML cells are known to express several of these transporters. 218 Rapamycin extrusion by ABC transporters could also account for marked differences in the drug concentration (range: from less than 1 nM to more than 100 nM) necessary to achieve IC 50 on AML blast clonogenic assay and could also explain why some patients did not respond at all to rapamycin treatment. 204 However, other mechanisms of rapamycin resistance have been identified.…”