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Pharmaceutics
Volume 14
Issue 5
10.3390/pharmaceutics14051042
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Article

3D Spheroids of Human Primary Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial Toxicity

by
Huifen Ding
1,2,
Kalyani Jambunathan
3,
Guochun Jiang
4,
David M. Margolis
4,
Iris Leng
5,
Michael Ihnat
6,
Jian-Xing Ma
7,
Jon Mirsalis
3 and
Yuanyuan Zhang
1,*
1
Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA
2
Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
3
SRI Biosciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA
4
University of North Carolina HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5
Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
6
Department of Pharmaceutical Sciences, The University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, USA
7
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC 27101, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Haiqing Dong
Pharmaceutics 2022, 14(5), 1042; https://doi.org/10.3390/pharmaceutics14051042
Received: 20 March 2022 / Revised: 21 April 2022 / Accepted: 28 April 2022 / Published: 11 May 2022
(This article belongs to the Special Issue Living Cell-Based Drug Delivery Systems for Biomedical Applications)
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Abstract

Mitochondrial toxicity (Mito-Tox) risk has increased due to the administration of several classes of drugs, particularly some life-long antiretroviral drugs for HIV+ individuals. However, no suitable in vitro assays are available to test long-term Mito-Tox (≥4 weeks). The goal of this study is to develop a 3D spheroid system of human primary urine-derived stem cells (USC) for the prediction of drug-induced delayed Mito-Tox. The cytotoxicity and Mito-Tox were assessed in 3D USC spheroids 4 weeks after treatment with antiretroviral drugs: zalcitabine (ddC; 0.1, 1 and 10 µM), tenofovir (TFV; 3, 30 and 300 µM) or Raltegravir (RAL; 2, 20 and 200 µM). Rotenone (RTNN, 10 µM) and 0.1% DMSO served as positive and negative controls. Despite only mild cytotoxicity, ddC significantly inhibited the expression of oxidative phosphorylation enzyme Complexes I, III, and IV; and RAL transiently reduced the level of Complex IV. A significant increase in caspase 3 and ROS/RNS level but a decrease in total ATP were observed in USC treated with ddC, TFV, RAL, and RTNN. Levels of mtDNA content and mitochondrial mass were decreased in ddC but minimally or not in TFV- and RAL-treated spheroids. Thus, 3D USC spheroid using antiretroviral drugs as a model offers an alternative platform to assess drug-induced late Mito-Tox. View Full-Text
Keywords: mitochondrial toxicity; 3D culture; spheroids; urine-derived stem cells mitochondrial toxicity; 3D culture; spheroids; urine-derived stem cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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MDPI and ACS Style

Ding, H.; Jambunathan, K.; Jiang, G.; Margolis, D.M.; Leng, I.; Ihnat, M.; Ma, J.-X.; Mirsalis, J.; Zhang, Y. 3D Spheroids of Human Primary Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial Toxicity. Pharmaceutics 2022, 14, 1042. https://doi.org/10.3390/pharmaceutics14051042

AMA Style

Ding H, Jambunathan K, Jiang G, Margolis DM, Leng I, Ihnat M, Ma J-X, Mirsalis J, Zhang Y. 3D Spheroids of Human Primary Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial Toxicity. Pharmaceutics. 2022; 14(5):1042. https://doi.org/10.3390/pharmaceutics14051042

Chicago/Turabian Style

Ding, Huifen, Kalyani Jambunathan, Guochun Jiang, David M. Margolis, Iris Leng, Michael Ihnat, Jian-Xing Ma, Jon Mirsalis, and Yuanyuan Zhang. 2022. "3D Spheroids of Human Primary Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial Toxicity" Pharmaceutics 14, no. 5: 1042. https://doi.org/10.3390/pharmaceutics14051042

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