Combination of disulfiram and Copper-Cysteamine nanoparticles induces mitochondria damage and promotes apoptosis in endometrial cancer

Lijun Yang; Cancan Yao; Zhenning Su; Yihao Fang; Nil Kanatha Pandey; Eric Amador; Tian Diao; Guo Bao; Derong Cao; Xihua Chen; Xiangbo Xu; Bin He; Yufeng Zheng; Wei Chen

doi:10.1016/j.bioactmat.2024.02.009

Combination of disulfiram and Copper-Cysteamine nanoparticles induces mitochondria damage and promotes apoptosis in endometrial cancer

Bioact Mater. 2024 Mar 1:36:96-111. doi: 10.1016/j.bioactmat.2024.02.009. eCollection 2024 Jun.

Authors

Lijun Yang^{1

2}, Cancan Yao^{1

2}, Zhenning Su^{1

2}, Yihao Fang³, Nil Kanatha Pandey^{4

5}, Eric Amador^{4

5}, Tian Diao^{1

2}, Guo Bao², Derong Cao³, Xihua Chen², Xiangbo Xu², Bin He², Yufeng Zheng^{1

6}, Wei Chen^{4

5}

Affiliations

¹ Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
² NHC Key Laboratory of Reproductive Health Engineering Technology Research, Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing 100081, China.
³ State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510641, China.
⁴ School of CHIPS, Xian-Jiaotong Liverpool University, Suzhou 215123, China.
⁵ Department of Physics, University of Texas at Arlington, Arlington, TX, 76013, USA.
⁶ School of Materials Science and Engineering, Peking University, Beijing, 100871, China.

Abstract

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, Cu₃Cl(SR)₂ (R[bond, double bond]CH₂CH₂NH₂), 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 in vitro experiments utilizing Ishikawa cells, in vivo 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 in vivo 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.

Keywords: Combination; Copper−Cysteamine nanoparticles; Disulfiram; Mitochondria damage; Promotes apoptosis in Endometrial Cancer.