MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation

Park, Sang Hyuk; Park, Chan‐Jeoung; Kim, Dae-Young; Lee, Bora; Kim, Young Jin; Cho, Young‐Uk; Jang, Seongsoo

doi:10.1016/j.leukres.2015.07.006

Cited by 6 publications

(7 citation statements)

References 20 publications

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“…The wild-type alleles (1236C/3435C/2677G) had higher Pgp activity and failed to achieve MMR. These data may explain the findings described before by Vasconcelos et al [ 39 ] and Park et al [ 41 ]. These authors had also shown the similarity between Pgp activity levels in CML cells and healthy individual cells as being indicative of poorer IM response.…”

Section: Abcb1 Polymorphisms (Snps) In Chronic supporting

confidence: 88%

“…By analyzing Pgp activity in CML samples from different subgroups (treatment failure and treatment response to IM), Park et al [ 41 ] revealed no differences among subgroups, or between PBMCs (from healthy individuals) and the patient groups ( p = 0.769). However, they found significantly higher Pgp expression in the subgroup showing IM failure ( p = 0.031).…”

Section: Clinical Relevance Of Abcb1 /Pgp Exprementioning

confidence: 99%

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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: Abcb1 Polymorphisms (Snps) In Chronic supporting

confidence: 88%

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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“…In our study, the prevalence of resistance to IM was 54.3%. This rate was relatively similar to a Tunisian study (49.2%) 29 but higher than the Korea study (16%) 30 . Consequently, we believe that Tunisian patients differ from other populations regarding resistance mechanisms to IM, secondarily to interethnic pharmacokinetic variation in IM response.…”

Section: Discussionsupporting

confidence: 76%

“…This rate was relatively similar to a Tunisian study (49.2%) 29 but higher than the Korea study (16%). 30 Consequently, we believe that Tunisian patients differ from other populations regarding resistance showed that the probability of achieving MMR was significantly higher in patients with b3a2 transcript. Our result emphasizes that CML patients with b3a2 transcript had less prospect to have failure responses to IM.…”

Section: Ta B L E 1 Clinical Characteristics Of Cml Patientsmentioning

confidence: 89%

Overexpression of P‐glycoprotein and resistance to Imatinib in chronic myeloid leukemia patients

Ammar

Louati²,

Frikha

et al. 2020

Clinical Laboratory Analysis

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Background The P‐glycoprotein (P‐gp) is one of the mechanisms of Imatinib (IM) resistance in chronic myeloid leukemia (CML). P‐gp has been identified as an efflux pump involved in releasing of IM outside CML cells. To date, the P‐gp involvement in the IM resistance development was not completely understood. Therefore, the present study aimed at measuring the P‐gp expression level on lymphocytes from Tunisian patients with CML and correlating this level with a molecular response to IM. Method The expression of P‐gp on peripheral blood lymphocytes from 59 Tunisian patients with CML (27 IM responder patients vs 32 IM non‐responder patients) was evaluated by flow cytometry. Result Our finding showed significantly positive expression of P‐gp in the lymphocytes from the IM non‐responder group when compared to the IM‐responder group (P = .001). In IM non‐responder CML patients, the comparison between CCyR achievers and non‐achievers showed a high mean fluorescence intensity (MFI) of P‐gp expression in patients who did not achieve their CCyR (P = .001). The comparison between patients with primary and secondary resistance to IM showed an increasing MFI value in patients with primary resistance to IM (P = .001). Besides, the comparison between nilotinib‐treated and dasatinib‐treated patients proved a high value of MFI in nilotinib‐treated patients (P = .001). Conclusion The overexpression of P‐gp on lymphocytes has significantly correlated with the failed molecular response to IM in patients with CML.

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“…The immunohistochemical findings demonstrated that Nrf2 and ABCB1 were significantly associated with disease-free survival. Previous studies have demonstrated an association between ABCB1 expression and chemotherapy resistance in colorectal cancer (49), breast cancer (50) and chronic myelogenous leukemia (51). Nrf2 expression significantly promotes tumor size, histological grade, distant metastasis and lymph node metastasis, and reduces sensitivity to chemotherapy or radiotherapy (8,17,52).…”

Section: Nuclear Accumulation Of P-fyn Follows Nrf2 Activationmentioning

confidence: 99%

Nrf2/p‑Fyn/ABCB1 axis accompanied by p‑Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non‑small cell lung cancer

et al. 2022

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Adjuvant cisplatin-vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP-binding cassette (ABC) sub-family B member 1 (ABCB1) and phosphorylated Fyn (p-Fyn) overexpression. However, the underlying mechanisms remain unclear. NF-E2-related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p-Fyn/ABCB1 axis in vinorelbine-resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH-DA assay. The total and subcellular expression of Nrf2, ABCB1 and p-Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p-Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin-vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p-Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease-free survival, and p-Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p-Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non-small cell lung cancer.

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MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation

Cited by 6 publications

References 20 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

Overexpression of P‐glycoprotein and resistance to Imatinib in chronic myeloid leukemia patients

Nrf2/p‑Fyn/ABCB1 axis accompanied by p‑Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non‑small cell lung cancer

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