The immunomodulatory properties and anticancer effects of disulfiram

Disulfiram acts as both a direct cytotoxic agent and an immunomodulator, making it a good candidate for combination therapies in cancer treatment.

Immunomodulation: DSF enhances the immune response by promoting the activation of CD8+ T cells, which are crucial for tumor immunity. It activates LCK, a kinase involved in TCR signaling, boosting the antitumor response. DSF also increases the expression of PD-L1 on tumor cells, which, when combined with PD-1 inhibitors, can enhance the immune checkpoint blockade therapy.

Macrophage Modulation: DSF suppresses macrophages' tumor-promoting activities by targeting FROUNT, a chemokine signaling regulator, and reprograms macrophages to produce antitumor cytokines like TNF-α and IFN-γ.

Copper-Dependent Antitumor Activity: Disulfiram forms complexes with divalent copper ions (Cu2+), which enhances its cytotoxicity against cancer cells. These complexes disrupt cancer cell functions by demethylating DNA, increasing antigen presentation, and inhibiting proteasome activity. This leads to an accumulation of cytotoxic proteins, causing cell death in tumor cells but sparing healthy cells with lower copper levels.

Reactive Oxygen Species (ROS) Induction: DSF increases ROS levels in cancer cells, disrupting their oxidative homeostasis and promoting apoptosis. This is achieved by inhibiting ROS scavenging pathways, leading to excessive ROS accumulation, which causes oxidative damage and cell death.

Inhibition of NF-κB Pathway: DSF suppresses the NF-κB pathway, which plays a role in cancer cell survival and chemoresistance. This inhibition sensitizes cancer cells to chemotherapy and promotes apoptosis, particularly in colorectal and breast cancers.

Activation of the JNK Pathway: DSF activates the c-Jun N-terminal kinase (JNK) pathway, which regulates apoptosis by increasing levels of phosphorylated JNK, c-Jun, and P38. This activation contributes to inhibiting cancer cell proliferation and promoting programmed cell death.

Proteasome Inhibition: The DSF-Cu2+ complex blocks the proteasomal degradation of proteins by targeting the NPL4/p97 pathway. This inhibition leads to the accumulation of misfolded proteins in cancer cells, triggering apoptosis.

Cell Cycle Arrest: DSF induces cell cycle arrest at various stages (G0/G1 or G2/M) in different cancer cells, inhibiting tumor growth. This arrest occurs through the modulation of oncogenes such as FOXO and MYC.

Induction of Immunogenic Cell Death (ICD): DSF promotes the release of calreticulin and heat shock proteins from tumor cells, facilitating the recruitment and activation of dendritic cells. This initiates a tumor-specific immune response, further promoting tumor cell death.

References

Zhang, S., Zong, Y., Chen, L. et al. The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics. Discov Onc 14, 103 (2023). https://doi.org/10.1007/s12672-023-00729-9

Popović, Kosta & Popović, Dušica & Miljković, Dejan & Popović, Jovan & Lalosevic, Dusan & Poša, Mihalj & Capo, Ivan. (2021). Disulfiram and metformin combination anticancer effect reversible partly by antioxidant nitroglycerin and completely by NF-κB activator mebendazole in hamster fibrosarcoma. Biomedicine & Pharmacotherapy. 143. 112168. 10.1016/j.biopha.2021.112168.