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Exploration of Verticillins in High-Grade Serous Ovarian Cancer and Evaluation of Multiple Formulations in Preclinical In Vitro and In Vivo Models

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Mol. Pharmaceutics 2023, 20, 6, 3049-3059
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    Exploration of Verticillins in High-Grade Serous Ovarian Cancer and Evaluation of Multiple Formulations in Preclinical In Vitro and In Vivo Models
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    • Elizabeth N. Kaweesa
      Elizabeth N. Kaweesa
      Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States
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      Orcidhttps://orcid.org/0000-0002-9799-646X
    • Jaqueline M. Bazioli
      Jaqueline M. Bazioli
      Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States
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      Orcidhttps://orcid.org/0000-0001-8219-8759
    • Herma C. Pierre
      Herma C. Pierre
      Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States
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    • Daniel D. Lantvit
      Daniel D. Lantvit
      Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States
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    • Samuel K. Kulp
      Samuel K. Kulp
      Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, Ohio 43210, United States
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    • Kasey L. Hill
      Kasey L. Hill
      Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States
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    • Mitch A. Phelps
      Mitch A. Phelps
      Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States
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    • Christopher C. Coss
      Christopher C. Coss
      Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States
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      Orcidhttps://orcid.org/0000-0002-8184-9190
    • James R. Fuchs
      James R. Fuchs
      Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States
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      Orcidhttps://orcid.org/0000-0002-8743-6389
    • Cedric J. Pearce
      Cedric J. Pearce
      Mycosynthetix, Inc., Hillsborough, North Carolina 27278, United States
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    • Nicholas H. Oberlies
      Nicholas H. Oberlies
      Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States
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      Orcidhttps://orcid.org/0000-0002-0354-8464
    • Joanna E. Burdette*
      Joanna E. Burdette
      Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States
      *Email: [email protected]. Phone: 312-996-6153.
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      Orcidhttps://orcid.org/0000-0002-7271-6847
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 6, 3049–3059
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    https://doi.org/10.1021/acs.molpharmaceut.3c00069
    Published May 8, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Verticillins are epipolythiodioxopiperazine alkaloids isolated from a fungus with nanomolar anti-tumor activity in high-grade serous ovarian cancer (HGSOC). HGSOC is the fifth leading cause of death in women, and natural products continue to be an inspiration for new drug entities to help tackle chemoresistance. Verticillin D was recently found in a new fungal strain and compared to verticillin A. Both compounds exhibited nanomolar cytotoxic activity against OVCAR4 and OVCAR8 HGSOC cell lines, significantly reduced 2D foci and 3D spheroids, and induced apoptosis. In addition, verticillin A and verticillin D reduced tumor burden in vivo using OVCAR8 xenografts in the peritoneal space as a model. Unfortunately, mice treated with verticillin D displayed signs of liver toxicity. Tolerability studies to optimize verticillin A formulation for in vivo delivery were performed and compared to a semi-synthetic succinate version of verticillin A to monitor bioavailability in athymic nude females. Formulation of verticillins achieved tolerable drug delivery. Thus, formulation studies are effective at improving tolerability and demonstrating efficacy for verticillins.

    Copyright © 2023 American Chemical Society

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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 6, 3049–3059
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.3c00069
    Published May 8, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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