3,6-Epidioxy-1,10-bisaboladiene induces ferroptosis-like cell death through lipid peroxidation

• Published in: Free radical research Vol. 57; no. 3; pp. 208 - 222
• Main Authors: Usukhbayar, Narandulam, Takano, Yukie, Uesugi, Shota, Muroi, Makoto, Osada, Hiroyuki, Kimura, Ken-ichi
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 04.03.2023
• Subjects: Caspases; Cell Death; Endoperoxide; Ferroptosis; Humans; Hydrogen Peroxide; Iron; Lipid Peroxidation; Necrosis; Endoperoxide; lipid peroxidation; ferroptosis
• ISSN: 1071-5762; 1029-2470
• DOI: 10.1080/10715762.2023.2229005

3,6-Epidioxy-1,10-bisaboladiene (EDBD) is a bisabolane sesquiterpene endoperoxide that was isolated from an edible wild plant in Japan, Cacalia delphiniifolia. It showed partially apoptotic cell death through caspase activation against HL-60 cells. However, almost all of the cells had necrotic morphology. Thus, we examined the mechanism of action of EDBD on necrotic cell death. EDBD induced ferrous ion-dependent cell death which causes cell membrane damage, and its cell death form was like H 2 O 2 -induced necrosis in HL-60 cells. The oxidative stress-induced necrosis inhibitor IM-54 prevented EDBD-induced cell death, but it was not blocked by either caspase inhibitor, z-VAD-fmk, or necroptosis inhibitor, necrostatin-1. Furthermore, EDBD induced lipid peroxidation in a time- and dose-dependent manner and was inhibited with both ferrostatin-1 and α-tocopherol. EDBD also downregulated GPX4, the primary cell defense protein against lipid peroxidation, and decreased GSH levels. Taken together, these results suggest that EDBD induces ferrous ion-dependent ferroptosis-like cell death through lipid peroxidation.