Top

Indian Journal of Hematology and Blood Transfusion

Published in:

01-12-2017 | Original Article

Pantoprazole Induces Apoptosis of Leukemic Cells by Inhibiting Expression of P-Glycoprotein/Multidrug Resistance-Associated Protein-1 Through PI3K/AKT/mTOR Signaling

Authors: Miao Liu, Rong Tang, Yi Jiang

Published in: Indian Journal of Hematology and Blood Transfusion | Issue 4/2017

Abstract

This study aims to investigate the effects and mechanism of pantoprazole on multidrug resistant leukemia K562/A02 and K562/ADM cell lines. K562/A02 and K562/ADM cells at logarithmic growth phase were pre-treated with different concentration of pantoprazole (0, 50, 100, 200 μg/mL) for 24 h. Flow cytometry was used to measure the cell growth cycle and apoptosis. RT-PCR and Western blot were used to measure the expression of p-PI3K, p-AKT, p-mTOR, P-glycoprotein (P-gp) and multidrug resistance-associated protein-1 (MRP1). Pantoprazole pretreatment significantly increased the ratio of G0/G1 phase but decreased the S phase of K562/A02 and K562/ADM cells in dose-dependent manner (p < 0.05). Flow cytometry analysis indicated that pretreatment of leukemic cells with pantoprazole induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analysis indicated that pantoprazole pretreatment inhibited the mRNA and protein expression of p-PI3K, p-Akt, p-mTOR, P-gp and MRP1 in K562/A02 and K562/ADM cells in a dose-dependent manner (p < 0.05). Pantoprazole arrested cell cycle and induced apoptosis of multidrug resistant leukemic cells by inhibiting the expression of P-gp and MRP1 through PI3K/Akt/mTOR signaling pathway.

Wu H, Kang H, Liu Y et al (2012) Roles of ABCB1 gene polymorphisms and haplotype in susceptibility to breast carcinoma risk and clinical outcomes. J Cancer Res ClinOncol. 138(9):1449–1462CrossRef

Agarwal S, Uchida Y, Mittapalli RK et al (2012) Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos 40(6):1164–1169CrossRefPubMedPubMedCentral

Vandamme T, Beyens M, de Beeck KO et al (2016) Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer 114(6):650–658CrossRefPubMedPubMedCentral

Badura S, Tesanovic T, Pfeifer H et al (2013) Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS ONE 8(11):e80070CrossRefPubMedPubMedCentral

Kampa-Schittenhelm KM, Heinrich MC, Akmut F et al (2013) Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia. Mol Cancer. 12(1):46CrossRefPubMedPubMedCentral

Martelli AM, Evangelisti C, Chappell W et al (2011) Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia 25(7):1064–1079CrossRefPubMed

Bailey KM, Wojtkowiak JW, Hashim AI, Gillies RJ (2012) Targeting the metabolic microenvironment of tumors. Adv Pharmacol 65:63–107CrossRefPubMedPubMedCentral

Shen W, Zou X, Chen M et al (2013) Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phospho-LRP6 expression in Wnt/β-catenin signaling. Oncol Rep 30(2):851–855CrossRefPubMed

LeBoeuf RA, Kerckaert GA (1986) The induction of transformed-like morphology and enhanced growth in Syrian hamster embryo cells grown at acidic pH. Carcinogenesis 7(9):1431–1440CrossRefPubMed

10.

Newell K, Franchi A, Pouysségur J et al (1993) Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci U S A. 90(3):1127–1131CrossRefPubMedPubMedCentral

11.

Zeng X, Liu L, Zheng M et al (2016) Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. Oncotarget. 7(16):22460–22473CrossRefPubMedPubMedCentral

12.

Louisa M, Soediro TM, Suyatna FD (2014) In vitro modulation of P-glycoprotein, MRP-1 and BCRP expression by mangiferin in doxorubicin-treated MCF-7 cells. Asian Pac J Cancer Prev 15(4):1639–1642CrossRefPubMed

13.

Chen M, Huang SL, Zhang XQ et al (2012) Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 113(7):2474–2487CrossRefPubMedPubMedCentral

14.

Wang ZC, Liu LZ, Liu XY et al (2015) Genetic polymorphisms of the multidrug resistance 1 gene MDR1 and the risk of hepatocellular carcinoma. Tumour Biol 36(9):7007–7015CrossRefPubMed

15.

Wolking S, Schaeffeler E, Lerche H et al (2015) Impact of genetic polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet 54(7):709–735CrossRefPubMed

16.

Brambila-Tapia AJ (2013) MDR1 (ABCB1) polymorphisms: functional effects and clinical implications. Rev Invest Clin 65(5):445–454PubMed

17.

Sane R, Agarwal S, Mittapalli RK et al (2013) Saturable active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system. J PharmacolExpTher. 345(1):111–124

18.

Lu JF, Pokharel D, Bebawy M (2015) MRP1 and its role in anticancer drug resistance. Drug Metab Rev 47(4):406–419CrossRefPubMed

19.

El-Sharnouby JA, Abou El-Enein AM, El Ghannam DM et al (2010) Expression of lung resistance protein and multidrug resistance-related protein (MRP1) in pediatric acute lymphoblastic leukemia. J Oncol Pharm Pract. 16(3):179–188CrossRefPubMed

20.

Mc Cubrey JA, Steelman LS, Chappell WH et al (2012) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget. 3(10):1068–1111CrossRef

21.

Barrett D, Brown VI, Grupp SA et al (2012) Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs 14(5):299–316PubMedPubMedCentral

22.

O’Gorman DM, McKenna SL, McGahon AJ et al (2001) Inhibition of PI3-kinase sensitises HL60 human leukaemia cells to both chemotherapeutic drug- and Fas-induced apoptosis by a JNK independent pathway. Leuk Res 25(9):801–811CrossRefPubMed

23.

Jazirehi AR, Vega MI, Chatterjee D et al (2004) Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin’s lymphoma B cells by Rituximab. Cancer Res 64(19):7117–7126CrossRefPubMed

24.

Ma H, Cheng L, Hao K et al (2014) Reversal effect of ST6GAL 1 on multidrug resistance in human leukemia by regulating the PI3K/Akt pathway and the expression of P-gp and MRP1. PLoS ONE 9(1):e85113CrossRefPubMedPubMedCentral

25.

Huang FF, Zhang L, Wu DS et al (2014) PTEN regulates BCRP/ABCG2 and the side population through the PI3K/Akt pathway in chronic myeloid leukemia. PLoS ONE 9(3):e88298CrossRefPubMedPubMedCentral

Title: Pantoprazole Induces Apoptosis of Leukemic Cells by Inhibiting Expression of P-Glycoprotein/Multidrug Resistance-Associated Protein-1 Through PI3K/AKT/mTOR Signaling
Authors: Miao Liu
Rong Tang
Yi Jiang
Publication date: 01-12-2017
Publisher: Springer India
Published in: Indian Journal of Hematology and Blood Transfusion / Issue 4/2017
Print ISSN: 0971-4502
Electronic ISSN: 0974-0449
DOI: https://doi.org/10.1007/s12288-017-0808-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

Validity of Estimation of Haemoglobin Content in Dried Blood Spot Samples

Discrepancy in Blood Grouping: Subgroups of B—Challenges and Dilemma

Evaluation of Coagulation Profile in Children with Type 1 Diabetes Mellitus Using Rotational Thromboelastometry

Predictors of Chemotherapy Related Toxicities in Elderly Lymphoma Patients: Experience from a Tertiary Cancer Centre

Protective Effect of Rituximab in Chronic Graft-Versus-Host Disease Occurrence in Allogeneic Transplant patients with Epstein Barr Virus Viremia

A Novel Double Heterozygous Hb D-Punjab/Hb J-Meerut Hemoglobinopathy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer