Natural withanolide-based lysine-specific demethylase 1 inhibitors for antitumor metastasis activity

• Published in: Phytochemistry letters 2022-06, Vol.49, p.93-98
• Main Authors: Zhang, Jinghan, Gu, Mengzhen, Ren, Chunling, Xu, Xiao, Kong, Lingyi, Li, Zhongrui, Han, Chao
• Format: Article
• Language: English
• Subjects: Anti-metastasis; Histone lysine demethylase; LSD1 inhibitor; Withaferin A; Withanolide
• ISSN: 1874-3900; 1876-7486
• DOI: 10.1016/j.phytol.2022.03.011

Lysine specific demethylase 1 (LSD1), which is overexpressed in several human cancers and acts as a demethylase of histone 3, lysine 4 and lysine 9, has become an attractive therapeutic target for cancer therapy. Based on our previous systematic studies, withanolides are important secondary metabolites mostly from the Solanaceae family of plants, which are crucial agents for cancer treatment. Here, withanolides were characterized as LSD1 inhibitors, especially withaferin A, with an IC50 value of 3.04 μM. In vitro bioactivity assays and virtual molecular docking indicated that withaferin A could inhibit MDA-MB-231 cell migration by inhibiting intracellular LSD1 activity. These findings provide a new withanolide-based natural molecular skeleton for LSD1 inhibitors with potential antitumor activity. [Display omitted] •Lysine specific demethylase 1 (LSD1) is a target for cancer therapy.•Natural withanolides are first characterized as LSD1 inhibitors.•Withaferin A can inhibit LSD1 activity with IC50 value of 3.04 μM.•Withaferin A also can inactive LSD1 activity in MDA-MB-231 cells.•Withaferin A may inhibit breast cancer cell proliferation and migration.