Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia

Abstract

The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp), codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML.

Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells

“…NaB treatment had different effects on the expression of ABC transporters, which have various substrates. For example, MRP1 and MRP2 export GSH-conjugated DNA alkylating agent, and MDR1 exports anthracyclines ( 11 – 14 ). The combination of NaB with DNA alkylating agents and/or other MRP1-3 substrates may lead to synergistic and more efficacious treatments.…”

“…Furthermore, a significant overlap has been reported in the substrate specificity of the ABC transporters. MDR1 extrudes natural toxins, antitumor drugs and drug metabolites ( 11 , 12 ), while MRPs export a variety of structurally diverse glutathione (GSH)-conjugates or therapeutic drugs ( 9 ). It has been revealed that MRP1-3 lead to resistance to hydrophobic and anionic compounds, including several natural compounds, whereas MRP4, MRP5 and MRP8 efflux cyclic nucleotides ( 13 , 14 ).…”

Effects of histone deacetylase inhibitors on ATP‑binding cassette transporters in lung cancer A549 and colorectal cancer HCT116 cells

“…ABC transporters associated with chemoresistance include MDR-1, MDR-associated proteins and breast cancer resistance protein, which are coded for by ABCB1, ABCCs and ABCG2, respectively (3). ABCB1 is the most well-known ABC transporter, and is able to extrude natural toxins, anticancer drugs and drug metabolites across the plasma membrane to confer an MDR phenotype in cancer cells (6)(7)(8). Similarly, ABCC members have been reported to confer chemoresistance in cancer cells by translocating a variety of structurally diverse glutathione conjugates or therapeutic drugs (4,9).…”

Metabolic Reprogramming During Multidrug Resistance in Leukemias

“…From those, the leucine-rich PPR motif-containing protein and MCM7, as well as the expression of ABCB1 could be used as markers to identify patients that would respond or fail to therapy with the tirosine kinase inhibitor, Imatinib ( 40 ). The importance of ABCB1 in the resistance to Imatinib in the clinical setting has been demonstrated ( 49 , 50 ), but it is not the only transporter involved. Tumor cells expressing ABCG2 are capable of Imatinib extrusion with great affinity ( 51 , 52 ).…”