Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice

Vasconcelos, Flavia da Cunha; Scheiner, Marcos Antônio Maurício; Moellman-Coelho, Arthur; Mencalha, André Luiz; Renault, Ilana Zalcberg; Rumjanek, Vivian M.; Maia, Raquel Ciuvalschi

doi:10.1016/j.leukres.2016.10.005

Cited by 21 publications

(15 citation statements)

References 43 publications

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“…The ABCB1 expression levels were analyzed and there was no difference between responder or non-responder patients. However, our group observed low ABCB1 mRNA levels in patients that achieved MMR at 12 months from the start of IM treatment [ 45 ]. In contrast, non-responder patients had the highest ABCB1 levels.…”

Section: Clinical Relevance Of Abcb1 /Pgp Exprementioning

confidence: 99%

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

et al. 2018

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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.

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Section: Clinical Relevance Of Abcb1 /Pgp Exprementioning

confidence: 99%

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

et al. 2018

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“…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 ).…”

Section: Mdr Chronic Myeloid Leukemia and Energy Metabolismmentioning

confidence: 99%

Metabolic Reprogramming During Multidrug Resistance in Leukemias

et al. 2018

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Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR) phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

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“…Lucena-1 and FEPS are cross-resistant to a diversity of compounds with natural and synthetic origins owing to, but not limited to, its high efflux activity mediated by the ABC transporters ABCB1 and ABCC1, and to imatinib mesylate as well, which has been demonstrated to increase ceramide and reduce sphingosine-1-phosphate levels on chronic myeloid leukemias (46). Resistance to that inhibitor associates to expression of ABCB1, however with no clear correlation to its efflux activity (47), which suggests that these cells manage their ceramides in alternative forms, involving or not ABCC1 in specific. In this context, ABCB1-mediated efflux activity was demonstrated to be disconnected from the translocation of ceramides on Golgi (48), and the ABCC1 inhibitor MK-571 was shown to affect retrograde membrane transport and to reduce GlcCer formation (49), evidences that point to at least partial involvement of ABCC in regulating sphingolipid levels.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

Salustiano

Costa

Freire-de-Lima

et al. 2020

Preprint

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Multidrug resistance (MDR) in cancer manifests due to cross-resistance to chemotherapeutic drugs with neither structural nor functional relationship, markedly by increased expression and activity of ABC superfamily transporters. Evidences indicate sphingolipids as substrates to ABC proteins in processes such as cell signaling, membrane biosynthesis and inflammation, and products of its biosynthetic route were shown to favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key cell regulator enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Under stress, cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after assimilation into GlcCer by UGCG. Given that cancer cells seem to mobilize UGCG and increase GSL contents for the clearance of ceramides ultimately contributing to treatment failure, we studied how inhibiting GSL biosynthesis would affect the MDR phenotype of chronic myeloid leukemias. Results indicate that MDR associates to higher expression of UGCG and to a complex GSL profile. Inhibition of this glucosyltransferase greatly reduced GM1 expression, and cotreatment with standard chemotherapeutics sensitized cells leading to mitochondrial membrane potential loss and apoptosis. Despite reducing ABCB1 expression, only the ABCC-mediated efflux activity was affected. Consistently, efflux of C6-ceramide, one byproduct of UGCG downregulation, was reduced after inhibition of ABCC-mediated transport. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, overcoming drug resistance through distinct mechanisms. This work brings more comprehension about the involvement of GSL for chemotherapy failure, and modulation of its contents emerges as an intervention targeted to MDR leukemias.

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Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice

Cited by 21 publications

References 43 publications

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

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

Metabolic Reprogramming During Multidrug Resistance in Leukemias

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

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