MDR1/P-glycoprotein in haematological neoplasms

Marie, Jean‐Pierre; Zhou, Da-Cheng; Gurbuxani, Sandeep; Legrand, Ollivier; Zittoun, R

doi:10.1016/0959-8049(96)00055-x

Cited by 63 publications

(43 citation statements)

References 60 publications

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“…However, their clinical usefulness is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1), belonging to the ATP-binding cassette protein family (Gottesman and Pastan, 1993;Germann, 1996;Marie et al, 1996;Borst et al, 2000). These transporters are responsible for the active ATP-dependent efflux of drugs out of resistant cells resulting in the decreased intracellular accumulation insufficient to inhibit resistant cell proliferation (Zaman et al, 1994;Paul et al, 1996).…”

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confidence: 99%

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells.

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The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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“…Although initially successful, resistance usually develops with time, resulting in relapse and treatment failure. Multidrug resistance (MDR) associated with overexpression of functional P-glycoprotein seems to be the most common resistance mechanism associated with relapsed AML (Baer and Bloomfield, 1991;Marie et al, 1996). The Pglycoprotein is a membrane-associated efflux pump that is able to reduce the intracellular drug accumulation of many chemically unrelated anti-tumour compounds (for review see Gottesman and Pastan, 1993).…”

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Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells

et al. 1999

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Summary Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein-expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL-60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5-1 µM and delayed mitotic cell death at 0.1 µM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50-100 µM daunorubicin and mitotic cell death at 10 µM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias.Keywords: drug resistance; P-glycoprotein; cell death; daunorubicin; myeloid leukaemia; response prediction 1090British Journal of Cancer (1999) 79(7/8), 1090-1097 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 25 February 1998 Revised 11 May 1998 Accepted 12 June 1998 Correspondence to: AK Larsen apoptotic morphological features and only very low levels of internucleosomal DNA fragmentation in the KG1 and KG1a cell lines (Quillet-Mary et al, 1996). Both KG1 and KG1a cells overexpress the MDR-1 gene as well as functional P-glycoprotein and are naturally resistant to daunorubicin compared with HL-60 or U937 cells. It has also been reported that another anthracycline, doxorubicin, induces internucleosomal fragmentation in parental P388 leukaemia cells but not in resistant P388/ADR cells that express the P-glycoprotein (Ling et al, 1993). These results can be interpreted in different ways. It is possible that P-glycoprotein expression and an altered cell death process represent two independent resistance mechanisms, which can occur together. Alternatively, the lack of apoptosis in MDR cells might be causally linked to the transport abnormalities as a minimum intracellular concentration of anthracycline may be required to trigger apoptosis...

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“…Overexpression of P-gp in tumor cells leads to an intracellular decrease of the cytotoxic agents [12]. P-gp was found to be overexpressed in various hematological malignancies including NHL [13]. Multiple investigators detected highlevel expression of P-gp in normal or abnormal NK cells using different methods [14][15][16][17].…”

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confidence: 99%

Immunohistochemical expression and clinical significance of P‐glycoprotein in previously untreated extranodal NK/T‐cell lymphoma, nasal type

Wang

et al. 2008

American J Hematol

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Overexpression of P-glycoprotein (P-gp) has been identified by a variety of methods in NK cells and NK malignancies. The aim of this study was to determine the clinical significance of P-gp in previously untreated extranodal NK/T-cell lymphoma, nasal type. Tumor specimens from 30 patients initially treated with CHOP or CHOP-based chemotherapy were examined by immunohistochemistry using JSB-1, a monoclonal antibody recognizing the intracellular epitope of P-gp molecule. Twenty cases (67%) were positive for P-gp expression. The complete response rate achieved in P-gp positive patients was significantly lower than in P-gp negative ones (20% vs. 60%, P = 0.045). With a median follow-up of 25 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 66 and 69%, respectively. Compared with both PFS and OS rates of P-gp positive patients, those of P-gp negative patients showed a trend of benefit that did not reach statistical significance for borderline P values (PFS: 90% vs. 54%, P = 0.1057; OS: 90% vs. 61%, P = 0.2028). Our results suggest that P-gp expression is related with poor treatment outcomes of extranodal NK/T-cell lymphoma, nasal type. Am. J. Hematol. 83:795-799, 2008. V

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MDR1/P-glycoprotein in haematological neoplasms

Cited by 63 publications

References 60 publications

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells

Immunohistochemical expression and clinical significance of P‐glycoprotein in previously untreated extranodal NK/T‐cell lymphoma, nasal type

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