Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells

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 activi...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 9; p. 4931
Main Authors:	Lica, Jan Jakub, Wieczór, Miłosz, Grabe, Grzegorz Jan, Heldt, Mateusz, Jancz, Marta, Misiak, Majus, Gucwa, Katarzyna, Brankiewicz, Wioletta, Maciejewska, Natalia, Stupak, Anna, Bagiński, Maciej, Rolka, Krzysztof, Hellmann, Andrzej, Składanowski, Andrzej
Format:	Journal Article
Language:	English
Published:	Basel MDPI AG 01-05-2021 MDPI
Subjects:	ABC transporters Bortezomib Cancer therapies Cell culture cell culture density-dependent cytological stage profile Cell density Cytotoxicity Doxorubicin Drug development drug screening platform effective drug concentration Ethanol Flow cytometry Laboratories Leukemia Light microscopy Morphology Optical microscopy primitive acute myeloid leukemia cellular stages primitive cancer cellular stages Selectivity selectivity index Stem cells Unit cell
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Summary:	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 density-related 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This authors equally contributed to this work.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms22094931