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Disulfiram/copper induces antitumor activity against gastric cancer cells in vitro and in vivo by inhibiting S6K1 and c-Myc

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Abstract

Purpose

Disulfiram (DSF) is an approved drug for the treatment of alcohol dependence. Accumulating evidence indicates that DSF, alone or in combination with copper (Cu), possesses strong antitumor activity in various malignancies. This study investigated the effects of DSF on gastric cancer (GC) and the potential mechanisms involved.

Methods

GC cell proliferation and apoptosis upon treatment with DSF with or without copper were analyzed using CCK-8 assay, colony formation assay, and flow cytometry. Glucose metabolism was investigated using glucose consumption and lactate production assays. The expression of caspase-3, Bcl-2, LC-3, P62, S6K1, c-Myc, GLUT1, PKM2, and LDHA was analyzed using western blot assay. In vivo nude mice studies were performed to verify the findings from in vitro analyses.

Results

Our study showed that DSF was highly toxic to GC cells in a Cu-dependent manner. Nontoxic concentrations of Cu enhanced the inhibitory effects of DSF on cell viability and colony formation. DSF also induced apoptotic and autophagic cell death in the presence of Cu. In addition, DSF/Cu inhibited glycolysis and xenograft growth of GC cells by suppressing the expression of S6K1, c-Myc, and their downstream molecules, including GLUT1, PKM2, and LDHA.

Conclusion

Our study demonstrated that DSF/Cu exerted antitumor activity against GC cells both in vitro and in vivo. DSF/Cu may represent a promising therapeutic strategy for the treatment of GC.

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Availability of data and material

All the data and materials will be available on reasonable request.

Abbreviations

GC:

Gastric cancer

DSF:

Disulfiram

GLUT1:

Glucose transporter type 1

HK2:

Hexokinase 2

PKM2:

Pyruvate kinase M2

LDHA:

L-lactate dehydrogenase A chain

IHC:

Immunohistochemistry

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Funding

This work was supported by National Natural Science Foundation of China (grant number 81702423), Postdoctoral Research Foundation of China (grant numbers 2017M623442 and 2018T111169), and Foundation of Shenyang Cancer Targeted Therapy Research Center (grant number 213463).

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Author notes

  1. Cheng Du, Xin Guan, and Yao Liu contributed equally to this study.

Authors and Affiliations

  1. Department of Oncology, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenyang, 110840, People’s Republic of China

    Cheng Du, Xin Guan, Yao Liu, Zhuxuan Xu, Xiaowei Du, Baolei Li, Meiling Wang & Zhendong Zheng

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  1. Cheng Du
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  2. Xin Guan
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  3. Yao Liu
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Correspondence to Zhendong Zheng.

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Du, C., Guan, X., Liu, Y. et al. Disulfiram/copper induces antitumor activity against gastric cancer cells in vitro and in vivo by inhibiting S6K1 and c-Myc. Cancer Chemother Pharmacol 89, 451–458 (2022). https://doi.org/10.1007/s00280-022-04398-3

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