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

Autor: Kaweesa EN; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States., Bazioli JM; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States., Pierre HC; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States., Lantvit DD; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States., Kulp SK; Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, Ohio 43210, United States., Hill KL; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States., Phelps MA; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States., Coss CC; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States., Fuchs JR; Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210, United States., Pearce CJ; Mycosynthetix, Inc., Hillsborough, North Carolina 27278, United States., Oberlies NH; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States., Burdette JE; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2023 Jun 05; Vol. 20 (6), pp. 3049-3059. Date of Electronic Publication: 2023 May 08.
DOI: 10.1021/acs.molpharmaceut.3c00069
Abstrakt: 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.
Databáze: MEDLINE
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