Study of copper-cysteamine based X-ray induced photodynamic therapy and its effects on cancer cell proliferation and migration in a clinical mimic setting

Copper-cysteamine as a new generation of sensitizers can be activated by light,X-rays,microwaves,or ultrasound to produce reactive oxygen species.X-ray induced photodynamic therapy(X-PDT)has been studied extensively;however,most of the studies reported so far were conducted in the laboratory,which is not conducive to the clinical translation conditions.In this contribution,for the first time,we investigated the treatment efficiency of copper-cysteamine(Cu-Cy)based X-PDT by mimicking the clinical conditions with a clinical linear accelerator and building deep-seated tumor models to study not only the effectiveness but also its effects on the cell migration and proliferation in the level of the cell,tissue,and animal.The results showed that,without X-ray irradiation,Cu-Cy nanoparticles(NPs)had a low toxicity in HepG2,SK-HEP-1,Li-7,and 4T1 cells at a concentration below 100 mg/L.Interestingly,for the first time,it was observed that Cu-Cy mediated X-PDT can inhibit the proliferation and migration of these cell lines in a dose-dependent manner.Antigen markers of migration and cell proliferation,proliferating cell nuclear antigen(PCNA)and E-cadherin,from tumor tissue in the X-PDT group were remarkably different from that of the control group.Furthermore,the MRI assessment showed that the Cu-Cy based X-PDT inhibited the growth of deeply located tumors in mice and rabbits(p<0.05)without any obvious toxicities in vivo.Overall,these new findings demonstrate that Cu-Cy NPs have a safe and promising clinical application prospect in X-PDT to improve the efficiency of radiotherapy(RT)for deep-seated tumors and effectively inhibit tumor cell proliferation and migration.

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

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,Cu_(3)Cl(SR)_(2)(R--CH_(2)CH_(2)NH_(2)),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 0.5μM 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.