Combination of the 6-thioguanine and disulfiram/Cu synergistically inhibits proliferation of triple-negative breast cancer cells by enhancing DNA damage and disrupting DNA damage checkpoint

• Published in: Biochimica et biophysica acta. Molecular cell research 2022-02, Vol.1869 (2), p.119169-119169, Article 119169
• Main Authors: Chu, Meiran, An, Xinglan, Zhang, Daoyu, Li, Qi, Dai, Xiangpeng, Yu, Hao, Li, Ziyi
• Format: Article
• Language: English
• Subjects: 6-TG; Acetaldehyde Dehydrogenase Inhibitors - pharmacology; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Copper - chemistry; Disulfiram - pharmacology; DNA Damage; DNA damage checkpoint; Drug Therapy, Combination; DSF/Cu; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B - genetics; NF-kappa B - metabolism; NF-кB inhibitor; Phosphorylation; Thioguanine - pharmacology; TNBC; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2021.119169

Because of the lack of specific molecular targeted therapies, triple-negative breast cancer (TNBC) has high tumour recurrence and metastasis rates. It is urgent to develop novel chemotherapeutic strategies to improve patient survival. DNA damaging agents have been shown to sensitize cancer to genotoxic chemotherapies. We first found that 6-thioguanine (6-TG) can activate the NF-кB signalling pathway. Our results showed that NF-кB signalling was reduced when cells were treated with 6-TG/disulfiram (DSF)/Cu. DSF/Cu enhanced the 6-TG-mediated inhibition of proliferation. 6-TG/DSF/Cu inhibited cell cycle progression, causing cell cycle arrest in the S phase and G2/M phase. Moreover, the combined effect of 6-TG and DSF/Cu induced apoptosis, and either agent alone was able to induce apoptosis. The accumulation of γH2A indicated that DSF/Cu increased the DNA damage induced by 6-TG. Combined treatment with 6-TG and DSF/Cu synergistically reduced the levels of both phosphorylated and total ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR), suggesting that DSF/Cu promoted 6-TG-induced DNA damage by suppressing ATR protein kinases, therefore enhancing cell apoptosis. In conclusion, we demonstrate that the combination of 6-TG and DSF/Cu exerted a significant synergistic antitumour effect on human TNBC in vitro and in vivo by enhancing DNA damage and disrupting DNA damage checkpoints. We propose that this combination therapy could be a novel strategy for the treatment of TNBC. •NF-кB signalling was reduced when cells were treated with 6-thioguanine /disulfiram/Cu.•6-Thioguanine/disulfiram/Cu reduced the viability and migration in cancer cells.•6-Thioguanine/disulfiram/Cu induced cell cycle arrest and cell apoptosis.•6-Thioguanine/disulfiram/Cu promoted DNA damage and disrupted DNA damage checkpoints.