有效药物浓度和选择性取决于原始细胞的比例。

Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells.

作者信息

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

机构信息

Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland.

Department of Physical Chemistry, Faculty of Chemistry, Gdansk University of Technology, 80-233 Gdansk, Poland.

出版信息

Int J Mol Sci. 2021 May 6;22(9):4931. doi: 10.3390/ijms22094931.

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 (IC and EC) 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 EC 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.

化疗药物在根除癌症干细胞（CSCs）方面效率低下，这推动了人们对更具活性和特异性化合物的探索。在这项工作中，我们展示了如何在药物开发流程中利用细胞密度依赖性阶段培养概况来获得更可靠的药物活性（IC和EC）结果。通过流式细胞术和光学显微镜，我们对HL-60、A-549和HEK-293衍生的亚系的细胞学阶段概况进行了表征，重点关注它们的原始细胞含量。然后，我们使用了一系列细胞毒性物质——C-123、硼替佐米、伊达比星、C-1305、多柔比星、二甲基亚砜和乙醇——来突出药物活性测定中典型的密度相关问题。我们还表明，以原始细胞含量标准化的药物EC和选择性指数是更准确的活性测量指标。我们通过计算一种新型化疗候选药物C-123的校正选择性指数来测试我们的方法。总体而言，我们的研究突出了在评估药物效率时考虑原始细胞分数的有用性。