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Sensitivity and Resistance to Therapy

Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin

Leukemia volume 14, pages 1444–1450 (2000)Cite this article

Abstract

Lovastatin, a competitive inhibitor of HMG-CoA reductase, reportedly inhibits proliferation and induces apoptosis of tumor cells with MDR-1 coded P-glycoprotein (Pgp) expression. In this study we investigated the sensitivity to lovastatin of eight myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic acid (RA) resistant subline NB4/RA, and their multidrug-resistant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and NB4/RA/MDR. MTT and apoptosis assays revealed that K-562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive to lovastatin than their parental cell lines, while NB4/MDR showed the same level of sensitivity as parental NB4 cells, which already were very sensitive to lovastatin. Significant elevation of transcript levels of HMG-CoA reductase was observed by semiquantitative RT-PCR analysis in more than three lovastatin-sensitive MDR sublines, but not in NB4/MDR compared with the parental cell lines. HMG-CoA reductase mRNA levels were up-regulated more than two-fold by the exposure to lovastatin in all of the parental non-Pgp-expressing cell lines. In NB4/MDR, HMG-CoA reductase mRNA level was elevated to a similar extent as in parental NB4, whereas in three other MDR sublines which showed preferential sensitivity to lovastatin, their HMG-CoA reductase mRNA levels were not significantly elevated after 24- and 48-h treatment with lovastatin. These results indicate a connection between drug resistance and regulation of the mevalonate pathway, and further strengthen the clinical possibility that drug resistant leukemias would be susceptible to treatment with lovastatin.

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Acknowledgements

We thank Dr Y Sugimoto (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan) for the generous assistance in transduction of MDR-1 gene vector into NB4 and NB4/RA cells. We also thank Dr Quang-Kim Tran for his helpful review of the manuscript.

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  1. Department of Medicine III, Hamamatsu University School of Medicine, 3600, Handa-cho, Hamamatsu, 431-3192, Japan

    L Maksumova, K Ohnishi, F Muratkhodjaev, W Zhang, L Pan, A Takeshita & R Ohno

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Maksumova, L., Ohnishi, K., Muratkhodjaev, F. et al. Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin. Leukemia 14, 1444–1450 (2000). https://doi.org/10.1038/sj.leu.2401856

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