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Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay
Published on: November 10, 2013
A powerful agonist for metal ion interference therapy: Multiple programs of cell death to amplify tumor
Yechen Huang1, Li Wang1, Jie Wu1
1Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.
Abstract:
Metal ion interference therapy (MIIT), which induces multiple programs of cell death, has emerged as a promising approach for combatting cancer. However, the efficient delivery of multiple metal ions and ion resistance by cellular metabolism present challenges, thereby impeding its progress. Herein, a novel MIIT initiator, layered double hydroxides composite, disulfiram (DSF)-loaded ZnCuAl-LDH, was constructed to efficiently co-deliver multiple metal ions and enhance the retention ability of metal ions within the cells. In an acidic environment, the ZCA-LDH@DSF initiator enabled pH-responsive release of Zn2+/Cu2+ and the DSF drug. On the one hand, Cu2+ and DSF in situ combined to form highly toxic CuET, inducing DNA damage and cell apoptosis. On the other hand, intracellular Cu2+ overload disrupted tricarboxylic acid cycle (TCA), leading to significant cuproptosis. Concurrently, intracellular Zn2+ inhibited the expression of the copper transport proteins ATP7A and ATP7B, reducing Cu2+ efflux and promoting intracellular Cu2+ accumulation, thereby further amplifying cuproptosis. Moreover, intracellular Zn2+ also induced pyroptosis via the caspase-1/gasdermin D (GSDMD)-dependent pathway, synergizing with CuET-induced cell apoptosis and cuproptosis to significantly enhance immunogenic cell death (ICD), which is favorable for MIIT in tumors. Therefore, ZCA-LDH@DSF demonstrated a remarkable ability to induce MIIT, thereby triggering multiple programs of cell death and inhibiting tumor growth and metastasis. Overall, the good biological safety and application prospect of ZCA-LDH@DSF initiator provide a new treatment model for combating tumor.
Insights
A novel layered double hydroxide composite, ZCA-LDH@DSF, efficiently delivers zinc and copper ions, triggering multiple cell death pathways like cuproptosis and pyroptosis for enhanced cancer therapy.
Area of Science:
- Biomedical Engineering
- Materials Science
- Oncology
Background:
- Metal ion interference therapy (MIIT) shows promise for cancer treatment by inducing cell death.
- Challenges include efficient delivery of multiple metal ions and cellular resistance.
- Developing novel delivery systems is crucial for advancing MIIT.
Purpose of the Study:
- To construct a novel MIIT initiator for efficient co-delivery of multiple metal ions.
- To enhance intracellular retention of metal ions and overcome cellular resistance.
- To investigate the synergistic effects of co-delivered ions and drugs on cancer cell death.
Main Methods:
- Fabrication of a disulfiram (DSF)-loaded ZnCuAl-layered double hydroxide (ZCA-LDH@DSF) composite.
- Evaluation of pH-responsive release of Zn2+, Cu2+, and DSF in acidic environments.
- Assessment of combined effects of Cu2+/DSF (CuET), Cu2+ overload (cuproptosis), and Zn2+ (pyroptosis) on cancer cells.
- Analysis of metal ion transport protein inhibition and immunogenic cell death (ICD) induction.
Main Results:
- ZCA-LDH@DSF enabled pH-responsive release of Zn2+/Cu2+ and DSF.
- Cu2+ and DSF formed toxic CuET, inducing DNA damage and apoptosis.
- Intracellular Cu2+ overload triggered cuproptosis by disrupting the TCA cycle.
- Zn2+ inhibited copper transport proteins, enhancing cuproptosis and inducing pyroptosis.
- Synergistic cell death pathways significantly enhanced ICD, inhibiting tumor growth and metastasis.
Conclusions:
- ZCA-LDH@DSF is an effective MIIT initiator for co-delivering multiple metal ions and drugs.
- The composite triggers multiple cell death programs, including apoptosis, cuproptosis, and pyroptosis.
- This approach enhances ICD and demonstrates significant potential for cancer treatment with good biological safety.
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