Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels

Mlejnek, Petr; Kosztyu, Petr; Doležel, Petr; Bates, Susan E.; Ruzickova, Eliska

doi:10.1016/j.cbi.2017.06.012

Cited by 25 publications

(21 citation statements)

References 46 publications

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“…Thus, resistance to anticancer drugs mediated by ABC transporters is proportional to their expressions at the protein level with the greater expression mediating greater resistance . Similarly, the inhibition efficacy of competitive inhibitors is inversely proportional to the ABC transporter expression level: cells expressing high drug transporter levels require higher concentrations of inhibitors to fully reverse the drug efflux . In addition, the hypersensitivity of MDR cancer cells to some drugs (collateral sensitivity), whose resistance is mediated by ABC transporters, depends on the expression level of drug transporters …”

Section: Discussionmentioning

confidence: 99%

Estimation of ABCB1 concentration in plasma membrane

Mlejnek

Kosztyu

Doležel

et al. 2019

J of Cellular Biochemistry

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The interaction between ABCB1 transporter and its substrates takes place in cell membranes but the available data precludes quantitative analysis of the interaction between transporter and substrate molecules. Further, the amount of transporter is usually expressed as a number of ABCB1 molecules per cell. In contrast, the substrate concentration in cell membranes is estimated by determination of substrate‐lipid partition coefficient, as examples. In this study, we demonstrate an approach, which enables us to estimate the concentration of ABCB1 molecules within plasma membranes. For this purpose, human leukemia K562 cells with varying expression levels of ABCB1 were used: drug selected K562/Dox and K562/HHT cells with very high transporter expression, and K562/DoxDR2, K562/DoxDR1, and K562/DoxDR05 cells with gradually decreased expression of ABCB1 derived from K562/Dox cells using RNA interference technology. First, we determined the absolute amount of ABCB1 in cell lysates using immunoblotting and recombinant ABCB1 as a standard. We then determined the relative portion of transporter residing in the plasma membrane using immunohistochemistry in nonpermeabilized and permeabilized cells. These results enabled us to estimate the concentration of ABCB1 in the plasma membrane in resistant cells. The ABCB1 concentrations in the plasma membrane of drug selected K562/Dox and K562/HHT cells containing the highest amount of transporter reached millimolar levels. Concentrations of ABCB1 in the plasma membrane of resistant K562/DoxDR2, K562/DoxDR1, and K562/DoxDR05 cells with lower transporter expression were proportionally decreased.

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Section: Discussionmentioning

confidence: 99%

Estimation of ABCB1 concentration in plasma membrane

Mlejnek

Kosztyu

Doležel

et al. 2019

J of Cellular Biochemistry

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“…The 48 identified human ABC transporter genes have been classified into seven subfamilies (ABC subfamilies A to G; Szakacs, Paterson, Ludwig, Booth-Genthe, & Gottesman, 2006). Of the 48 ABC transporters, some have a broad substrate specificity and have the potential to transport a range of anticancer agents and affect the expression level of these transporters in tumor cells, resulting in drug resistance (Mlejnek, Kosztyu, Dolezel, Bates, & Ruzickova, 2017). The Cancer Genome Atlas database reveals that ABCG2 expression ranges over 1,000-fold in a variety of tumor types (Robey et al, 2018).…”

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confidence: 99%

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Tsai

Chang

Tsai

et al. 2018

Journal Cellular Physiology

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In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

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“…Notably, it has recently been demonstrated that the inhibition efficiency of competitive inhibitors of ABCB1 depend on the expression level of ABCB1. Thus, cells expressing high levels of the transporter require higher concentrations of competitive inhibitors to achieve the same reversal of the drug efflux [ 66 ]. These findings might also be applicable for ABCG2.…”

Section: Discussionmentioning

confidence: 99%

Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review

Nielsen

Palshof

Brünner

et al. 2017

IJMS

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Background: One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients. Results: Few studies have evaluated the association between ABCG2 gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, n = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of ABCG2 mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high ABCG2 tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan. Conclusion: The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning ABCG2 mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed.

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Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels

Cited by 25 publications

References 46 publications

Estimation of ABCB1 concentration in plasma membrane

Estimation of ABCB1 concentration in plasma membrane

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review

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