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

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  • Ding, Huifen
    • Other Affiliation: Wake Forest University Health Sciences
  • Jambunathan, Kalyani
    • Other Affiliation: SRI International
  • Jiang, Guochun
    • Affiliation: HIV Cure Center
  • Margolis, David M.
    • Affiliation: HIV Cure Center
  • Leng, Iris
    • Other Affiliation: Wake Forest School of Medicine
  • Ihnat, Michael
    • Other Affiliation: University of Oklahoma
  • Ma, Jian-Xing
    • Other Affiliation: Wake Forest University
  • Mirsalis, Jon
    • Other Affiliation: SRI International
  • Zhang, Yuanyuan
    • Other Affiliation: Wake Forest University Health Sciences
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.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Pharmaceutics
Journal volume
  • 14
Journal issue
  • 5
Page start
  • 1042
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  • English
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  • Publisher
ISSN
  • 1999-4923

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