Disulfiram/Copper Combination as a Potential Therapeutic Approach for Hepatocellular Carcinoma: Targeting the
Jing Cao1, Jing Deng1, Xinhua Li1
1Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
Abstract:
Hepatocellular carcinoma (HCC) represents a major public health issue globally, necessitating the urgent development of new therapies. The therapeutic efficacy of disulfiram (DSF) and copper (Cu) in HCC was investigated in the present study, focusing on cytotoxicity, mitochondrial function, and apoptosis to clarify the mechanistic basis of this drug combination. Our findings revealed a significant, dose-dependent reduction in HCC cell viability with DSF/Cu treatment. Further investigation showed increased reactive oxygen species (ROS) levels, decreased adenosine triphosphate (ATP) production, and a decline in mitochondrial membrane potential (MMP). These events culminated in the activation of caspase-9 and caspase-3, key enzymes in the apoptotic pathway, leading to cell death. Mechanistically, DSF/Cu synergistically increased the expression of activating transcription factor 3 (ATF3), a known tumor suppressor, in HCC cells. In vivo studies using a mouse tumor model supported these findings, demonstrating significantly inhibited tumor growth in the DSF/Cu group compared with the control group. Overall, our study findings suggest that the DSF/Cu combination exhibits significant therapeutic potential against HCC by modulating the ATF3-dependent mitochondrial apoptosis pathway, a strategy that warrants further preclinical exploration.
Insights
The disulfiram and copper combination effectively reduced liver cancer cell viability and tumor growth. This therapy targets the ATF3-dependent mitochondrial apoptosis pathway, showing promise for hepatocellular carcinoma treatment.
Area of Science:
- Hepatocellular Carcinoma Research
- Cancer Therapeutics
- Mitochondrial Apoptosis
Background:
- Hepatocellular carcinoma (HCC) is a global health concern requiring novel therapeutic strategies.
- Existing treatments for HCC have limitations, driving the search for new drug combinations.
Purpose of the Study:
- To investigate the therapeutic efficacy of disulfiram (DSF) and copper (Cu) in hepatocellular carcinoma (HCC).
- To elucidate the mechanistic basis of the DSF/Cu combination, focusing on cytotoxicity, mitochondrial function, and apoptosis.
Main Methods:
- Assessed HCC cell viability, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) production, and mitochondrial membrane potential (MMP) following DSF/Cu treatment.
- Investigated the activation of caspase-9 and caspase-3, key apoptotic enzymes.
- Examined the expression of activating transcription factor 3 (ATF3) in HCC cells.
- Evaluated tumor growth inhibition in vivo using a mouse tumor model.
Main Results:
- DSF/Cu treatment significantly reduced HCC cell viability in a dose-dependent manner.
- The combination therapy increased ROS levels, decreased ATP production, and lowered MMP, triggering apoptosis via caspase-9 and caspase-3 activation.
- DSF/Cu synergistically upregulated ATF3 expression in HCC cells.
- In vivo studies confirmed significant inhibition of tumor growth with DSF/Cu treatment.
Conclusions:
- The DSF/Cu combination demonstrates significant therapeutic potential against HCC.
- This drug combination effectively modulates the ATF3-dependent mitochondrial apoptosis pathway, leading to cancer cell death and tumor growth inhibition.
- Further preclinical investigation of the DSF/Cu combination as an HCC therapy is warranted.
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