Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.057
Cremastranone-Derived Homoisoflavanes Suppress the Growth of Breast Cancer Cells via Cell Cycle Arrest and Caspase-Independent Cell Death
Yeram Choi1,†, Sangkyu Park2,†, Seul Lee3, Ha-Eun Shin1, Sangil Kwon3, Jun-Kyu Choi2, Myeong-Heon Lee1, Seung-Yong Seo3,* and Younghee Lee1,2,*
1Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju 28644,
2Biotechnology Research Institute, Chungbuk National University, Cheongju 28644,
3College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
*E-mail: yhl4177@cbnu.ac.kr (Lee Y), syseo@gachon.ac.kr (Seo SY)
Tel: +82-43-261-3387 (Lee Y), +82-32-820-4949 (Seo SY)
Fax: +82-43-267-2306 (Lee Y), +82-32-820-4829 (Seo SY)
†The first two authors contributed equally to this work.
Received: March 14, 2023; Revised: April 17, 2023; Accepted: April 19, 2023; Published online: May 25, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Breast cancer is the most common cancer and a frequent cause of cancer-related deaths among females globally. As therapeutic strategies for breast cancer have limitations, novel chemotherapeutic reagents and treatment strategies are needed. In this study, we investigated the anti-cancer effect of synthetic homoisoflavane derivatives of cremastranone on breast cancer cells. Homoisoflavane derivatives, SH-17059 and SH-19021, reduced cell proliferation through G2/M cell cycle arrest and induced caspaseindependent cell death. These compounds increased heme oxygenase-1 (HO-1) and 5-aminolevulinic acid synthase 1 (ALAS1), suggesting downregulation of heme. They also induced reactive oxygen species (ROS) generation and lipid peroxidation. Furthermore, they reduced expression of glutathione peroxidase 4 (GPX4). Therefore, we suggest that the SH-17059 and SH-19021 induced the caspase-independent cell death through iron accumulation from heme degradation, and the ferroptosis might be one of the potential candidates for caspase-independent cell death.
Keywords: Breast cancer, Cremastranone, Homoisoflavane, Cell cycle arrest, Caspase-independent cell death, Anti-cancer

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