Probing the Cytotoxic Signaling Induced by Eupenifeldin in Ovarian Cancer Models

J Nat Prod. 2023 Sep 22;86(9):2102-2110. doi: 10.1021/acs.jnatprod.3c00186.

Amanda C Maldonado ¹, Monica A Haughan ², Manead Khin ², Julia Ekiert ², Ziwei Zhang ², Daniel Lantvit ², Zeinab Y Al Subeh ³, Herma C Pierre ⁴, Maryna Salkovski ⁵, Tal Hirschhorn ⁶, Yu Gao ², Cedric J Pearce ⁷, Brent R Stockwell ⁶ ⁸, Leslie N Aldrich ⁵, Nicholas H Oberlies ⁴, Joanna E Burdette ²

Affiliations

1 Chicago Biomedical Consortium, Northwestern University, Evanston, Illinois 60208, United States.
2 Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
3 Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid 22110, Jordan.
4 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
5 Department of Chemistry, College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
6 Department of Biological Sciences, Columbia University, New York, New York 10027, United States.
7 Mycosynthetix Inc., Hillsborough, North Carolina 27278, United States.
8 Department of Chemistry, Columbia University, New York, New York 10027, United States.

PMID: 37643353 DOI: 10.1021/acs.jnatprod.3c00186

Abstract

High-grade serous ovarian Cancer (HGSOC) is the most common and lethal ovarian Cancer histotype. Lack of early detection methods, limited therapeutic agents, and low 5-year survival rate reflect the urgent need to develop new therapies. Eupenifeldin, a bistropolone, originally isolated from Eupenicillium brefeldianum, is a cytotoxic Fungal metabolite. In three HSGOC cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC₅₀ value less than 10 nM, while 10 times higher concentrations were required for cytotoxicity in nontumorigenic fallopian tube secretory epithelial cell lines (FTSEC). An in vivo hollow fiber assay showed significant cytotoxicity in OVCAR3. Eupenifeldin significantly increased Annexin V staining in OVCAR3 and -8, but not OVCAR5. Eupenifeldin activated caspases 3/7 in OVCAR3, OVCAR5, and OVCAR8; however, cleaved PARP was only detected in OVCAR3. Quantitative proteomics performed on OVCAR3 implicated Ferroptosis as the most enriched cell death pathway. However, validation experiments did not support Ferroptosis as part of the cytotoxic mechanism of eupenifeldin. Autophagic flux and LC3B puncta assays found that eupenifeldin displayed weak autophagic induction in OVCAR3. Inhibition of Autophagy by cotreatment with bafilomycin reduced the toxicity of eupenifeldin, supporting the idea that induction of Autophagy contributes to the cytotoxic mechanism of eupenifeldin.

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