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Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells

Abstract

Poor efficiency of chemotherapeutics in the eradication of Cancer Stem Cells (CSCs) has been driving the search for more active and specific compounds. In this work, we show how cell density-dependent stage culture profiles can be used in drug development workflows to achieve more robust drug activity (IC50 and EC50) results. Using flow cytometry and light microscopy, we characterized the cytological stage profiles of the HL-60-, A-549-, and HEK-293-derived sublines with a focus on their primitive cell content. We then used a range of cytotoxic substances—C-123, bortezomib, idarubicin, C-1305, doxorubicin, DMSO, and ethanol—to highlight typical densityrelated issues accompanying drug activity determination. We also showed that drug EC50 and selectivity indices normalized to primitive cell content are more accurate activity measurements. We tested our approach by calculating the corrected selectivity index of a novel chemotherapeutic candidate, C-123. Overall, our study highlights the usefulness of accounting for primitive cell fractions in the assessment of drug efficiency.

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Category:
Articles
Type:
artykuły w czasopismach
Published in:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES no. 22,
ISSN: 1661-6596
Language:
English
Publication year:
2021
Bibliographic description:
Lica J., Wieczór M., Grabe G. J., Heldt M., Jancz M., Misiak M., Gucwa K., Brankiewicz W., Maciejewska N., Stupak A., Bagiński M., Rolka K., Hellmann A., Składanowski A.: Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells// INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES -Vol. 22,iss. 9 (2021), s.4931-
DOI:
Digital Object Identifier (open in new tab) 10.3390/ijms22094931
Sources of funding:
  • Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, fund number: 531-T060-D737-21
Verified by:
Gdańsk University of Technology

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