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Screening of an annotated compound library for drug activity in a resistant myeloma cell line

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Abstract

Purpose: Resistance to anticancer drugs is a major problem in chemotherapy. In order to identify drugs with selective cytotoxic activity in drug-resistant cancer cells, the annotated compound library LOPAC1280, containing compounds from 56 pharmacological classes, was screened in the myeloma cell line RPMI 8226 and its doxorubicin-resistant subline 8226/Dox40. Methods: Cell survival was measured by the Fluorometric Microculture Cytotoxicity Assay. Results: Selective cytotoxic activity in 8226/Dox40 was obtained for 33 compounds, with the most pronounced difference observed for the glucocorticoids. A microarray analysis of the cells showed a difference in mRNA-expression for the glucocorticoid receptor suggesting potential mechanisms for the difference in glucocorticoid sensitivity. In the presence of the glucocorticoid-receptor antagonist RU486, the sensitivity to the glucocorticoids was reduced and a similar effect level in RPMI 8226 and 8226/Dox40 was achieved. Conclusion: In conclusion, screening of mechanistically annotated compounds on drug-resistant cancer cells can identify compounds with selective activity and provide a basis for the development of novel treatments of drug-resistant malignancies.

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Acknowledgements

The skilful technical assistance of Maria Rydåker, Christina Leek and Lena Lenhammar is gratefully acknowledged. This study was supported by the Swedish Cancer Society, the Swedish Research Council, the Lions Cancer Research Fund, Beijer foundation, Wallenberg Consortium North, Marcus Borgström Foundation, Swedish Society for Medical Research, Göran Gustafsson Foundation, Carl Tryggers Foundation, Stockholm Cancer Society and Swedish Knowledge Foundation. Conflict of interest statement—None declared.

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Authors and Affiliations

  1. Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, 751 85, Uppsala, Sweden

    Linda Rickardson, Caroline Haglund, Henrik Lövborg & Rolf Larsson

  2. Department of Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden

    Mårten Fryknäs, Mats G. Gustafsson & Anders Isaksson

  3. Department of Oncology, Radiology and Clinical Immunology, Uppsala University, 751 85, Uppsala, Sweden

    Peter Nygren

  4. Department of Engineering Sciences, Uppsala University, 751 85, Uppsala, Sweden

    Mats G. Gustafsson

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  1. Linda Rickardson
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Correspondence to Linda Rickardson.

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Rickardson, L., Fryknäs, M., Haglund, C. et al. Screening of an annotated compound library for drug activity in a resistant myeloma cell line. Cancer Chemother Pharmacol 58, 749–758 (2006). https://doi.org/10.1007/s00280-006-0216-7

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  • DOI: https://doi.org/10.1007/s00280-006-0216-7

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