Evodiamine Exhibits Anti-Bladder Cancer Activity by Suppression of Glutathione Peroxidase 4 and Induction of Ferroptosis

Abstract

Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase 4 (GPX4) expression, under EVO treatment. Our results showed that EVO inhibited the cell proliferation of poorly differentiated, high-grade bladder cancer TCCSUP cells in a dose- and time-dependent manner. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Given the features of iron dependency and lipid-peroxidation-driven death in ferroptosis, the iron chelator deferoxamine (DFO) was used to suppress EVO-induced ferroptosis. The lipid peroxide level significantly decreased when cells were treated with DFO prior to EVO treatment. DFO also attenuated EVO-induced cell death. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Furthermore, EVO suppressed the migratory ability, decreased the expression of mesenchymal markers, and increased epithelial marker expression, determined by a transwell migration assay and Western blotting. The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. In conclusion, EVO is a novel inducer for activating the ferroptosis of bladder cancer cells and may be a potential therapeutic agent for bladder cancer.

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

“…During ferroptosis, highly reactive free radicals are generated by iron, which cause lipid peroxidation and damage to the cell membrane [226][227][228][229][230][231][232][233][234][235][236][237][238]. In this context, chelating drugs [239][240][241], other chelators, iron [242][243][244][245][246] and related metabolic pathways [247][248][249] and associated biomolecules [250][251][252][253][254][255] can play a major role in the modulation of ferroptosis and influence the treatment of all associated diseases. Similar considerations and interests are also developed by clinical scientists working on microbial diseases, where iron appears to be a major component and regulator of microbial growth, and in this context chelating drugs can play an important role in antimicrobial treatments [256][257][258][259][260].…”

The Interplay between Medical Plants and Gut Microbiota in Cancer

“…In particular, the pathogenesis of cancer is linked to a reduction in anti-inflammatory bacteria like Lactobacillus, Roseburia, Akkermansia muciniphila, and Eubacterium, and to an increase in the growth of proinflammatory species like Ruminococcus gnavus and Bacteroidetes. The mechanism at the base of dysbiosis is the break of gut-barrier integrity that promotes the translocation of bacteria fragments like lipopolysaccharide (LPS) to the blood, with consequences on systemic inflammation, oxidative state, cellular immunity, and metabolism (Figure 2) [19][20][21][22][23][24][25][26][27][28].…”