ATP binding cassette C1 (ABCC1/MRP1)-mediated drug efflux contributes to disease progression in T-lineage acute lymphoblastic leukemia

Abstract

Purpose In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by ATPase Binding Cassette (ABC) proteins, which principally involve ABCB1 (multidrug resistance 1, MDR1) and ABCC1 (multidrug resistance protein 1, MRP1). However, direct comparisons between the differential effects of ABCB1 and ABCC1 have been difficult, since identical cell lines with differential expression of these transporters have not been developed. Experimental Design In this study, we developed and compared the biological profiles of Jurkat cell lines that selectively over-expressed ABCB1 and ABCC1. Vincristine (VCR) plays an important role in the treatment of T-lineage ALL (T-ALL), and is often the first drug given to newly-diagnosed patients. Because of its importance in treatment, we provided escalating, sub-lethal doses of VCR to Jurkat cells, and extended our observations to expression profiling of newly diagnosed patients with T-ALL. Results We found that VCR-resistant cells over-expressed ABCC1 nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells actively extruded VCR, and that ABCC1-mediated drug resistance conferred a different spectrum of multidrug resistance than other T-ALL induction agents. siRNA experiments that blocked ABCC1 export confirmed that VCR resistance could be reversed in vitro. Analyses of T-lymphoblasts obtained from 92 newly diagnosed T-ALL patients treated on Children's Oncology Group Phase III studies 8704/9404 showed that induction failure could be explained in all but one case by the over-expression of ABCB1 or ABCC1. Conclusions Taken together, these results suggest that over-expression of ABC transporters plays a contributing role in mediating treatment failure in T-ALL, and underscore the need to employ alternate treatment approaches in patients for whom induction failed or for those with relapsed disease.

Pharmacogenomics of Vincristine‐Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

“…Our analyses revealed that the ADME variant with the strongest evidence for an association with VIPN, rs3784867 ( P = 5.34 × 10 −5 ; OR = 4.91; 95% CI = 1.99–12.10), occurs in the intron of ABCC1 . This gene encodes multidrug resistance protein 1, a protein, which is involved in both transport of, and resistance to, vincristine . ABCC1 has also been implicated in anthracycline‐related and methotrexate‐related pharmacogenomic phenotypes .…”

A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells

“…For the above reasons, it is difficult to find a feasible transmembrane transport protein reversal agent in clinical practice. At present, many researchers have focused on new chemical sensitizers or new methods to specifically down-regulate the expression of multidrug resistance genes, such as small molecule inhibitors, natural drugs, RNA interference, epigenetic regulation, or signal transduction pathways [27,33,34,35,36,37].…”

Generation and Characterization of anAbcc1Humanized Mouse Model (hABCC1flx/flx) with Knockout Capability

“…Nevertheless, ABCC1 also plays a role in the chemoresistance of different cancers. For instance, high ABCC1 expression is a negative prognostic factor in cases of soft tissue sarcoma (Citti et al, 2012;Martin-Broto et al, 2014) and acute myeloid and lymphoblastic leukemia (van der Kolk et al, 2000;Winter et al, 2013;Liu et al, 2018). Furthermore, this correlation has been shown for neuroblastoma patients.…”