Yang Lijun, Yao Cancan, Su Zhenning, Fang Yihao, Pandey Nil Kanatha, Amador Eric, Diao Tian, Bao Guo, Cao Derong, Chen Xihua, Xu Xiangbo, He Bin, Zheng Yufeng, Chen Wei
Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing 100081, China.
Bioact Mater. 2024 Mar 1;36:96-111. doi: 10.1016/j.bioactmat.2024.02.009. eCollection 2024 Jun.
Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, CuCl(SR) (R[bond, double bond]CHCHNH), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing experiments utilizing Ishikawa cells, studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 μM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.
子宫内膜癌（EC）是影响女性的最常见妇科恶性肿瘤之一，其发病率和疾病相关死亡率呈稳步上升趋势。双硫仑（DSF）是一种经美国食品药品监督管理局（FDA）批准的主要用于治疗酒精成瘾的药物，已显示出有前景的抗肿瘤特性。研究表明DSF具有增强的抗肿瘤活性，尤其是与铜联合使用时。新型铜-半胱胺（CuCy）化合物CuCl(SR)（R[键，双键]CHCHNH）具有光动力效应，并在包括紫外线、X射线、微波和超声波照射等各种条件下显示出显著的抗肿瘤潜力。本研究深入探讨了利用铜-半胱胺与DSF联合对抗子宫内膜癌的协同抗肿瘤作用及其潜在机制。该研究涉及全面分析，包括利用 Ishikawa 细胞的实验、研究以及转录组分析。值得注意的是，两种化合物以0.5 μM的低剂量联合给药在抑制肿瘤生长、抑制血管形成和刺激细胞凋亡方面表现出显著疗效。特别是，在裸鼠体内进行的移植瘤实验清楚地证明了这种联合治疗具有显著的抗肿瘤作用。通过透射电子显微镜进行的详细检查揭示了线粒体损伤、细胞肿胀和破裂的有力证据，表明联合治疗导致了形态学上的凋亡变化。此外，转录组分析在分子水平上揭示了线粒体相关基因的大量下调，以及DNA修复途径的显著受阻。这些发现强烈表明，CuCy和DSF的联合应用可诱导Ishikawa细胞中的线粒体损伤，从而促进细胞凋亡并最终产生强大的抗肿瘤作用。
