![]() Over the last decade, the value of inducing ferroptosis, as well as its linkage with cancer therapy, has been noticed. GPX4 catalyzes the conversion of lipid peroxide at the expense of glutathione to prevent cells from undergoing ferroptosis.Ĭancer cells are usually under constant oxidative stress, yet ferroptosis seldom occurs due to the delicate equilibrium between catalytic irons and thiols. RS元 acts as a ferroptosis inducer by inactivating glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme that protects cells against membrane lipid peroxidation. In this process, iron serves as a catalytic agent to convert peroxides into free radicals. It occurs when cells encounter ambient oxidative stress, with the massive membrane lipid peroxidation compromising the selective permeability of the plasma membrane. Ferroptosis is an iron-dependent and lipid-peroxidation-driven form of cell death. Previous studies have revealed that EVO exerts its cytotoxic effect by increasing the amount of reactive oxygen species (ROS) in cancer cells, and ROS can be amplified in a positive feedback loop. However, the precise mechanism of this multifaceted anti-cancer activity of EVO remains obscure. EVO causes G2/M cell cycle arrest and suppresses tumor cell invasion and metastasis. It is suggested that EVO acts in synergy with a target therapy or chemotherapeutic agents when multidrug resistance occurs in tumor cells. However, the literature discussing the anti-cancer effect of EVO in bladder UC is currently limited. It has been demonstrated to exhibit anti-cancer activities in non-small-cell lung cancer, hepatocellular carcinoma (HCC), leukemia, and breast cancer. Evodiamine (EVO), one of the quinazoline alkaloids, is an essential isolated from the seeds of Evodia rutaecarpa (Wu-Zhu-Yu). Some natural compounds extracted from herbs have been considered as potential adjuvants to enhance the anti-neoplastic ability of current medication. 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. ![]() The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. 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. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. DFO also attenuated EVO-induced cell death. The lipid peroxide level significantly decreased when cells were treated with DFO prior to 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. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. 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. 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. Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation however, little is known about its underlying mechanism. ![]()
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