Guan Jing-Song, Jia Jing, Huang Ze-Xiu, Zhou Yu-Qing, Zheng Jing-Jie, Lin Qi-Man, Wang Yi-Fei, Fan Jiang-Lin, Wang Yao
Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, China.
College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
Front Pharmacol. 2025 Feb 24;16:1536375. doi: 10.3389/fphar.2025.1536375. eCollection 2025.
Ferroptosis is an intracellular iron-dependent cell death that is distinct from apoptosis, necrosis, and autophagy. Increasing evidence indicated that ferroptosis plays a crucial role in suppressing tumors, thus providing new opportunities for cancer therapy. The drug cepharanthine, commonly used to treat leukopenia, has been discovered to function as an anticancer agent to multiple types of cancer via diverse mechanisms. However, the effect of cepharanthine on prostate cancer remains unclear.
A semi-synthetic derivative of cepharanthine, cepharanthine hydrochloride (CH), is used in this study due to its better water solubility and bioavailability. The prostate cancer cell lines LNCaP, 22Rv1, PC3 and xenograft mouse models are used for detecting the anti-tumor effect of CH and . Types of cell death including ferroptosis are detected by flow cytometry using annexin V and total/lipid reactive oxygen species probes, drug combination of CH with ferroptosis inhibitor/ion chelator, and the appearance of mitochondria under a transmission electron microscopy. The mechanism is investigated by high-throughput transcriptome analysis and transcription factor function analysis of androgen receptor.
CH inhibits cellular functions and trigger ferroptosis in prostate cancer cells. Mechanistic research revealed both common and distinct pharmacological mechanisms of CH-induced ferroptosis in different prostate cancer cells. High-throughput transcriptome analysis revealed that ferroptosis-related genes are significantly regulated in androgen receptor-dependent cells 22Rv1 and LNCaP, and less significantly in androgen receptor-independent cell PC3. Furthermore, CH was found to reduce the gene expressions and protein levels of GPX4 and FSP1 through modulating the activity of the androgen receptor signaling pathway, but not through its transcription factor activity. In addition, CH upregulated ACSL4 and downregulated DHODH, with the combined regulatory outcomes synergistically inducing ferroptosis. An experiment employing CH and ion chelator-treated nude mice validated the mechanism by which CH induces ferroptosis to combat prostate cancer.
This study has identified CH as a novel ferroptosis-inducing agent for the treatment of prostate cancer. The multiple mechanisms we found provides strong evidence for the eventual clinical application of the drug.
铁死亡是一种细胞内铁依赖性细胞死亡，不同于凋亡、坏死和自噬。越来越多的证据表明，铁死亡在抑制肿瘤中起关键作用，从而为癌症治疗提供了新的机会。药物千金藤素通常用于治疗白细胞减少症，现已发现它通过多种机制对多种类型的癌症发挥抗癌作用。然而，千金藤素对前列腺癌的影响仍不清楚。
本研究使用千金藤素的半合成衍生物盐酸千金藤素（CH），因其具有更好的水溶性和生物利用度。前列腺癌细胞系LNCaP、22Rv1、PC3和异种移植小鼠模型用于检测CH的抗肿瘤作用。通过使用膜联蛋白V和总/脂质活性氧探针的流式细胞术、CH与铁死亡抑制剂/离子螯合剂的药物组合以及透射电子显微镜下线粒体的外观来检测包括铁死亡在内的细胞死亡类型。通过高通量转录组分析和雄激素受体的转录因子功能分析来研究其机制。
CH抑制前列腺癌细胞的细胞功能并引发铁死亡。机制研究揭示了CH在不同前列腺癌细胞中诱导铁死亡的共同和独特药理机制。高通量转录组分析表明，铁死亡相关基因在雄激素受体依赖性细胞22Rv1和LNCaP中受到显著调控，而在雄激素受体非依赖性细胞PC3中调控作用较小。此外，发现CH通过调节雄激素受体信号通路的活性来降低GPX4和FSP1的基因表达和蛋白水平，而不是通过其转录因子活性。此外，CH上调ACSL4并下调DHODH，联合调控结果协同诱导铁死亡。一项使用CH和离子螯合剂处理裸鼠的实验验证了CH诱导铁死亡以对抗前列腺癌的机制。
本研究确定CH为一种新型的诱导铁死亡治疗前列腺癌的药物。我们发现的多种机制为该药物最终的临床应用提供了有力证据。
