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Biochem Biophys Res Commun. 2019 Jun 11;513(4):891-897. doi: 10.1016/j.bbrc.2019.03.192. Epub 2019 Apr 16.

Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate.

Author information

1
Department of Immunology, School of Life Sciences and Biopharmaceuticals Engineering, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
2
Centre Laboratory, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Digital Quality Evaluation of Chinese Medical of State Administration of TCM, Guangzhou, 510006, PR China.
3
Biology Department, Wesleyan College, 4760 Forsyth Road, Macon, GA, 31210, USA.
4
Key Laboratory of Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China.
5
Department of Immunology, School of Life Sciences and Biopharmaceuticals Engineering, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Digital Quality Evaluation of Chinese Medical of State Administration of TCM, Guangzhou, 510006, PR China. Electronic address: hychen@gdpu.edu.cn.

Abstract

BACKGROUND:

Disulfiram (DSF), a drug widely used to control alcoholism, which has anticancer activity by inducing apoptosis in a copper (Cu)-dependent manner. Numerous evidences from mouse experiments indicated that some anti-cancer agents of chemotherapeutic drugs favor the induction of immunogenic cancer cell death (ICD) leading to tumor-specific immune responses. However, whether DSF could induce the colorectal tumor cells death and the mechanism involved in ICD regulatory remains elusive. The main objective of this study was to elucidate the effect of DSF/Cu on the apoptosis of colorectal cancer (CRC) cells and the expression of the two major ICD markers in CRC cells: calreticulin (CRT) and heat shock proteins (HSP) 70.

METHODS:

Firstly, the toxicity of DSF/Cu in HCT116, SW620 and HCT8 cells was assayed by MTT. Flow cytometry was utilized to detect the apoptosis effects. The effects of DSF/Cu on the expression of ICD-related molecules in tumor tissues were further verified in the CRC xenograft mouse model.

RESULTS:

The results showed that DSF/Cu increase apoptosis of these three cells in a dose dependent manner and significantly inhibited the proliferation at the concentration range from 0.05 to 1.6 μM. Furthermore, the expression of CRT and HSP70 on the cell surface also increased. The rate of transplanted tumors grew slowly, and the expression of CRT and HSP70 in colorectal cancer tissues was increased after treated with DSF/Cu.

CONCLUSION:

In conclusion, our results show that DSF/Cu exerts anti-colorectal cancer and its underlying mechanisms are associated with the enhancement of molecules expression of cell ICD. These results provide experimental evidence and theory basis of therapy for developing the DSF/Cu as the drug for CRC.

KEYWORDS:

Cancer immunity; Colorectal cancer; Copper; Disulfiram; Immunogenicity of tumor cell death

PMID:
31003768
DOI:
10.1016/j.bbrc.2019.03.192

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