Chen Xiaohui, Kadier Mairehaba, Shi Mengting, Li Kefeng, Chen Hongtao, Xia Yongzhen, Wang Qiaohua, Li Rongna, Long Yili, Qin Jingbo, Wang Hao, Jiang Guanmin
Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China.
Center for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macau SAR, 999078, China.
Small. 2025 Jun;21(22):e2408996. doi: 10.1002/smll.202408996. Epub 2025 Apr 26.
Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria-melatonin (Mito-Mel) significantly increases its potency by over 1000-fold. Mito-Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.
雄激素剥夺治疗后，前列腺癌常进展为去势抵抗性前列腺癌（CRPC），这是一个重大的临床挑战。靶向肿瘤代谢，特别是线粒体途径，为克服CRPC提供了一种有前景的策略。将褪黑素（Mel）修饰为三苯基膦（TPP）阳离子靶向线粒体的褪黑素（Mito-Mel），可使其效力显著提高1000多倍。Mito-Mel选择性靶向线粒体，增强活性氧（ROS）生成并导致线粒体膜电位破坏。这导致线粒体呼吸受到抑制，包括三羧酸（TCA）循环和氧化磷酸化（OXPHOS），进而抑制CRPC存活代谢适应，如糖酵解。体外和体内实验首次表明，通过TPP靶向线粒体的天然小分子化合物通过诱导肿瘤细胞焦亡和促进免疫反应，展现出优异的抗癌疗效，突显了该策略对有效治疗CRPC的令人鼓舞的前景。
