Original article
Cyclosporine diminishes multidrug resistance in K562/ADM cells and improves complete remission in patients with acute myeloid leukemia

https://doi.org/10.1016/j.biopha.2008.10.008Get rights and content

Abstract

This study was designed to investigate the effects of cyclosporine A (CsA) on a multidrug resistance cultured cell line, and its effect on complete remission in patients with acute myeloid leukemia (AML). A multidrug resistant K562/ADM cell line and drug-sensitive K562 cell line was used. The intracellular concentration of daunorubicin and the accumulation of Rhodamine 123 (Rh123) in the K562/ADM and K562 cells were evaluated. Clinical effects of CsA were also studied in 65 patients with AML. In the K562/ADM cells, the 50% of inhibition concentration (IC50) of daunorubicin only group was 23.0 ± 5.2 μmol/L, which was greater than in other groups co-administered with CsA (1.2 ± 4.8 μmol/L), verapamil (1.5 ± 5.4 μmol/L) or CsA + verapamil (1.4 ± 4.3 μmol/L) (all P < 0.01). The relative fluorescence intensity of Rh123 in the K562/ADM cells treated with CsA and daunorubicin was increased from 48.9% to 69.8% (P < 0.05). CsA also improved the complete remission rate in the AML patients (72.7% vs 21.9%, P < 0.01). We conclude that CsA can significantly diminish the multidrug resistance in K562/ADM cells. It also enhances the complete remission rates in patients with AML. CsA may be used as an integral part of the chemotherapy for AML.

Introduction

Multidrug resistance to cytotoxic drugs is the main cause for the failure of chemotherapy of acute myeloid leukemia (AML). Cellular expression of the multidrug transporter, P-glycoprotein is recognized as a biological mechanism contributing to treatment failure in AML [1], [2]. P-glycoprotein is expressed in approximately 40% of relapsed AML, which was higher than other types of leukemia or normal lymphocytes [3]. In cells expressing P-glycoprotein, there is an increased extrusion of cytotoxic drugs, leading to poor response to standard chemotherapy and adverse clinical outcomes in AML [1], [2].

In vitro studies have shown that cyclosporine A (CsA) is able to restore the concentration of chemotherapeutic drugs in target cancer cells [4]. CsA was found to enhance retention of the substrate drug mitoxantrone in cells overexpressing P-glycoprotein and increase the cytotoxicity of mitoxantrone [5]. However, whether the restoration of intracellular drug concentration is related to CsA's suppressive effect on P-glycoprotein expression or function has been controversial. Some studies suggested that factors other than P-glycoprotein, such as delays in systemic clearance of cytotoxic drugs, are responsible for the daunorubicin or idarubicin accumulation in AML blasts [6], [7].

In this study, we evaluated the drug resistance reversing effect of CsA in a cultured cell line. The influence of CsA on intracellular concentration of daunorubicin as well as the function of P-glycoprotein in these cells was also investigated. Finally, the clinical effects of CsA on the complete remission rates in a group of patients with AML were studied.

Section snippets

Materials and methods

This study was approved by the institution review board of Liaocheng People's Hospital. Written informed consent, was obtained from all participating patients.

Effect of CsA on multidrug resistance in K562/ADM cells

As shown in Table 1, the IC50 of daunorubicin in the K562/ADM cells treated with CsA, verapamil, or CsA + verapamil was significantly less than the IC50 in the control (daunorubicin only) group (P < 0.01). There was no significant difference in the IC50 between CsA, verapamil and CsA + verpamil groups (P > 0.05).

Effect of CsA on intracellular concentration of daunorubicin in K562/ADM cells

As shown in Fig. 1, the intracellular concentration of daunorubicin in the multidrug resistant K562/ADM cells was significantly lower than in the drug-sensitive K562 cells. CsA increased the

Discussion

The main findings of this study are: 1) CsA had a significant suppressing or reversing effect on multidrug resistance in K562/ADM cells in vitro; 2) CsA increased the intracellular concentration of daunorubicin in the multidrug resistant K562/ADM cells; 3) CsA treatment increased the fluorescence intensity of Rh123 in the K562/ADM cells; 4) addition of CsA to the conventional remission induction regimen increased the rate of complete remission and total effective rate in patients with AML.

Acknowledgement

This study was supported by a research grant from Shandong Provincial Science and Technology Development Projects (No: 2007GG20002011).

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    Citation Excerpt :

    They reported on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumor model where the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and CyA. CyA may be used as an integral part of the chemotherapy for acute myeloid leukemia (AML) due to its ability to significantly diminish the multidrug resistance in K562/ADM cells and enhance the complete remission rates in patients with AML (Li et al., 2009). Use of CyA as a reverter of multidrug resistance may produce short-term improvement of antitumor activity but may also induce enhancement of tumor metastasis (Van de Vrie et al., 1997).

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