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Synergistic effects of verapamil and anti-mdr1 ribozyme on reversion of multidrug resistance in the P-glycoprotein-positive K562 cell line

Leukemia volume 15, pages 696–697 (2001)Cite this article

One of the underlying mechanisms of multidrug resistance (MDR) is over expression of mdr1 gene and its production of P-glycoprotein (Pgp) which acts as a drug efflux pump. Therefore, a key step for reversal of MDR is to inhibit the Pgp synthesis and function. One of the strategies to overcome multidrug resistance is the combination of anticancer agents with a modulator. Verapamil, for example, is an effective modulator and is able to bind to Pgp and block the Pgp function. Nevertheless, high-dose verapamil is required for effective reversal of MDR phenotype, dose-related cardiovascular toxicities limit its clinical application unfortunately.1 Therefore, a new strategy to overcome Pgp-mediated MDR phenotype has been studied. One means to intercept a target mRNA is to use a catalytic RNA, or ribozyme. Hammerhead ribozymes are able to recognize a GUC sequence in target RNA molecule and cleave it. The anti-mdr1 hammerhead ribozyme has been reported to be an effective approach in inhibiting mdr1 expression and reversing drug resistance, but reversion of drug resistance was only partially effective.234 To solve these problems, we studied the effect of combining two different reversal methods, noted above, to reverse MDR.

The amount of Pgp on the cell surface was quantitatively analyzed by flow cytometry as described.5 The results are shown in Table 1. The fluorescence intensity of Pgp expression in the transfected K562R cells with anti-mdr-1 ribozyme was lower than that of untransfected parent cells. This indicated that the expression of Pgp in ribozyme transfected K562R cells had decreased. The empty vector did not alter Pgp expresssion. Levels of Pgp expression by flow cytometric analyses were consistant with those of RT-PCR.

Table 1  Pgp expression in transfected cells measured with anti-MDR monclone antibody C219
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Acknowledgements

We thank KJ Scanlon for support. This work was supported by a grant from the Chinese Academy of Sciences (KJ951-B1–610).

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Authors and Affiliations

  1. Department of Hematology, the First Affiliated Hospital, West China University of Medical Science, Chengdu, PR China

    Y Gong

  2. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Science, Chinese Academy of Sciences, Shanghai, PR China

    Y Gong, W Han, J Liu & Y Jin

  3. Leukemia Unit, Ren Ji Hospital Shanghai Second Medical University, Shanghai, PR China

    F Chen, J Han & R Ou Yong

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Gong, Y., Han, W., Liu, J. et al. Synergistic effects of verapamil and anti-mdr1 ribozyme on reversion of multidrug resistance in the P-glycoprotein-positive K562 cell line. Leukemia 15, 696–697 (2001). https://doi.org/10.1038/sj.leu.2402072

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