P‐glycoprotein is expressed and causes resistance to chemotherapy in <scp>EBV</scp>‐positive T‐cell lymphoproliferative diseases

Yoshimori, Mayumi; Takada, Honami; Imadome, Ken‐Ichi; Kurata, Morito; Yamamoto, Kouhei; Koyama, Takatoshi; Shimizu, Norio; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako

doi:10.1002/cam4.494

Cited by 28 publications

(28 citation statements)

References 39 publications

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“…Both aripiprazole and dehydro‐aripiprazole are substrates of P‐glycoprotein (P‐gp) . Gene ABCB1 (ATP‐binding cassette subfamily B 1) encodes P‐gp that is involved in drug absorption, distribution and elimination . C3435T SNP (rs1045642) in ABCB1 is related to level of expression and function of ABCB1, and thereby drug plasma concentrations.…”

mentioning

confidence: 99%

Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

Belmonte

Ochoa

Román

et al. 2018

Basic Clin Pharma Tox

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The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC , C and t of aripiprazole were higher and clearance of aripiprazole, AUC of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC (p = 0.039) and C of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.

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mentioning

confidence: 99%

Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

Belmonte

Ochoa

Román

et al. 2018

Basic Clin Pharma Tox

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“…Additionally, it has been identified that the abnormal expression of P-gp and MRP1 on the surface of the cell membrane may impair tumor chemosensitivity and lead to MDR by removing chemotherapy drugs from tumor cells (13)(14)(15)(16). Overexpression of P-gp and MRP1 in tumor tissues has been associated with poor response to clinical chemotherapy in T-cell lymphoma (15,17). The results of the present study also demonstrated that the expression of P-gp and MRP1 was significantly downregulated in Jurkat and Hut-78 cells treated with celecoxib compared with those that were not treated with celecoxib, indicating that celecoxib may inhibit the efflux of intracellular anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

Celecoxib enhances sensitivity to chemotherapy drugs of T‑cell lymphoma

Yang

Zhao

et al. 2018

Oncol Lett

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Abstract. Celecoxib is a newly-identified nonsteroidal anti-inflammatory drug, which has been used to treat fever in clinical practice. Celecoxib has been demonstrated to suppress the viability of various human tumor cells. However, the effect of celecoxib on response of T-cell lymphoma to chemotherapy agents remains unclear. The aim of the present study was to investigate the effect of celecoxib on chemosensitivity of human T-cell lymphoma, and to address the underlying mechanism of action. The cytotoxicity of CDDP, epirubicin and VCR on Jurkat and Hut-78 cells treated with celecoxib was assessed by MTT assay, and the half-maximal inhibitory concentration (IC 50 ) value was calculated by Origin 75 software. The effect of celecoxib on apoptosis and intracellular concentration of Rhodamine-123 in Jurkat and Hut-78 cells was analyzed by flow cytometry. The expression of transcription factor p65 (p65), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) at mRNA and protein levels were detected by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Proliferation suppression rates and apoptosis levels were significantly increased in Jurkat and Hut-78 cells combined with celecoxib compared with those without celecoxib, when treated with CDDP, epirubicin and VCR. The IC 50 values of the chemotherapy agents were lower in Jurkat and Hut-78 cells treated with celecoxib compared with those that were not.The apoptosis level, expression of Bax and the intracellular concentration of Rhodamine-123 were increased, whereas the expression of p65, Bcl-2, MDR1 and MRP1 were decreased, in celecoxib-treated Jurkat and Hut-78 cells compared with those without celecoxib treatment. These results indicated that celecoxib may enhance the sensitivity of T-cell lymphoma to chemotherapy drugs by inhibiting the expression of multidrug resistance (MDR)-associated proteins via downregulating the activity of the nuclear factor-κB signaling pathway, suggesting that celecoxib may improve the curative effect of chemotherapy drugs in T-cell lymphoma.

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“…The immune cells in the patients with hematological malignancies, such as acute myeloid leukemia (AML), diffuse large B Cell lymphoma, multiple myeloma, and follicular lymphoma, demonstrate enhanced expression of P-gp, thus making these cancers resistant to chemotherapy (108,109). Enhanced expression of P-gp in myeloid and lymphoid lineage cells of AML and B-cell lymphomas, respectively, is associated with upregulation of MAPkinase/ERK signaling (110).…”

Section: P-gp Function In Tumor Immunitymentioning

confidence: 99%

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

2020

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Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor M 2-macrophages and, anti-tumor NK-cell and Th17/CD4 + T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.

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P‐glycoprotein is expressed and causes resistance to chemotherapy in EBV‐positive T‐cell lymphoproliferative diseases

Cited by 28 publications

References 39 publications

Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

Celecoxib enhances sensitivity to chemotherapy drugs of T‑cell lymphoma

Perplexing Role of P-Glycoprotein in Tumor Microenvironment

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