The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1
Yeting Hu1, Yucheng Qian1, Jingsun Wei1
1Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.
Insights
Disulfiram combined with copper effectively inhibits colorectal cancer (CRC) cell growth by inducing autophagy, not apoptosis. This combination offers a potential new treatment strategy for CRC, targeting the ULK1 pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) presents a significant global health burden with limited therapeutic options.
- Autophagy induction is an emerging strategy for cancer treatment.
- Disulfiram (DSF), an antialcohol medication, shows anti-tumor properties in various cancers.
Purpose of the Study:
- To investigate the efficacy of disulfiram combined with copper (DSF/Cu) in treating colorectal cancer (CRC).
- To elucidate the mechanism by which DSF/Cu affects CRC cells, specifically regarding autophagy and apoptosis.
- To identify novel therapeutic targets for CRC treatment.
Main Methods:
- In vitro and in vivo studies were conducted using colorectal cancer models.
- Whole genome CRISPR library screening was employed to identify key molecular pathways.
- Cell viability, autophagy markers, and apoptosis were assessed.
Main Results:
- DSF/Cu significantly inhibited colorectal cancer cell viability both in vitro and in vivo.
- The primary mechanism of action was the induction of autophagy, rather than apoptosis.
- Whole genome CRISPR screening identified ULK1 as a crucial mediator in DSF-induced autophagy.
Conclusions:
- DSF/Cu demonstrates potent anti-cancer effects against colorectal cancer by inducing autophagy.
- The ULK1 pathway is a key target for DSF-mediated autophagy in CRC.
- This study provides a promising therapeutic strategy for colorectal cancer treatment.
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