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DDTC-Cu(I) Nano-MOF Induces Ferroptosis by Targeting SLC7A11/GPX4 Signal in Colorectal Cancer
Juan Huang1, Mingjing Yang1, Xingyu Zhou1
1Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Abstract:
Drug repurposing has received increasing attention in the field of oncology drug development as an alternative strategy to de novo drug synthesis. Disulfiram (DSF) has a long history of clinical application in alcohol withdrawal, and recent studies have revealed that its metabolite diethyldithiocarbamate (DDTC) can be coordinated with copper ions in vivo to form Cu-DDTC complexes with anticancer activity. However, the insufficient in vivo stability of DSF remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with DDTC-Cu(I) chemical valence and polycrystalline structure was prepared by incorporation of DDTC into the nanosized metal-organic framework (MOF) Cu-BTC. The in vitro cellular evaluation results showed that Cu-BTC@DDTC exhibited high inhibition of tumor cell growth, migration, and invasion. Animal experiments on the xenograft tumor model further demonstrated the excellent antitumor activity and biosafety of Cu-BTC@DDTC, and the antitumor activity was found to be closely related to the regulation of the SLC7A11/GPX4 signaling pathway to induce ferroptosis. This study provides a feasible option for antitumor drug development based on a drug repurposing strategy.
Insights
Disulfiram
Area of Science:
- Oncology
- Drug Development
- Nanomedicine
Background:
- Drug repurposing offers an alternative to de novo cancer drug synthesis.
- Disulfiram (DSF), an alcohol withdrawal drug, and its metabolite diethyldithiocarbamate (DDTC) show anticancer potential via copper complexes.
- In vivo instability of DSF is a significant challenge.
Purpose of the Study:
- To develop a stable nanomedicine for enhanced anticancer efficacy.
- To investigate the antitumor activity and mechanism of a novel Cu-BTC@DDTC nanomedicine.
Main Methods:
- Incorporation of DDTC into the nanosized metal-organic framework (MOF) Cu-BTC to form Cu-BTC@DDTC.
- In vitro cellular assays for tumor cell growth, migration, and invasion.
- In vivo xenograft tumor model experiments to evaluate antitumor activity and biosafety.
Main Results:
- Cu-BTC@DDTC demonstrated significant inhibition of tumor cell growth, migration, and invasion in vitro.
- In vivo studies confirmed excellent antitumor activity and biosafety of Cu-BTC@DDTC.
- Antitumor effects were linked to SLC7A11/GPX4 pathway regulation, inducing ferroptosis.
Conclusions:
- The novel Cu-BTC@DDTC nanomedicine shows promising anticancer properties.
- This approach leverages drug repurposing for effective cancer therapy development.
- Targeting the SLC7A11/GPX4 pathway is a key mechanism for ferroptosis induction.
