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 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.
Highlights
Since the HL-60 line of Acute Myeloid Leukemia (AML) cells is well characterized in terms of developmental stage profiles, we chose it as a reference line to study the stage-dependent quantitative aspects of drug efficiency
By comparing the IC50 and EC50 values obtained for A-549 to those obtained for healthy embryonic kidney cells HEK-293, we found that C-123, bortezomib, doxorubicin, and C-1305 all had selectivity indices lower than 1, indicating higher cytostatic activity in embryonic than cancer cells (Tables 4–6)
Research of Cancer Stem Cells (CSCs) based on the etiology of AML has the potential to translate into more effective therapies aimed at eliminating the cell stage responsible for the initiation and relapse of the disease [87]
Summary
The stem cell theory of cancer states that some cancerous cells proliferate and sustain cell population to stem cells in healthy organs and tissues. The idea that cancer is primarily driven by a small population of stem cells has important implications [1,2]. Acute Myeloid Leukemia (AML), one of the most studied and best understood malignancies, has well-described cellular stages. Despite numerous malfunctions at the cellular level, the hierarchical development of AML with retained ability to differentiate still resembles the hematopoietic process [3,4]. The AML leukemogenesis and its initiation by a Leukemia Initiation Cells (LICs) can occur either during embryogenesis or later in life, e.g., 4.0/)
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