Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Zheng, Xin; Liu, Zijian; Mi, Mi; Wen, Qiuyue; Wu, Gang; Zhang, Liling

doi:10.3389/fonc.2021.734853

Cited by 19 publications

(15 citation statements)

References 54 publications

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“…Probably, the generation of Cu(DETC) 2 might reduce the expression and activity of DNA methyltransferase 1 (DNMT1), leading to the epigenetic reactivation of interferon regulatory factor 7 (IRF7) and subsequent PD‐L1 upregulation through the axis of DNMT1/IRF7/PD‐L1. [ 30 ] Moreover, we also investigated the capacity of CuCH‐NCs/DSF combination to induce immunogenic cell death (ICD) effect for augmenting antitumor immune response. [ 31 ] Clearly, the 2.5‐fold increase of calreticulin (CRT) on the cell surface, 3.8‐fold decrease of intranuclear high mobility group protein B1 (HMGB1), and 2.2‐fold increase of extracellular ATP level were respectively observed in the 4T1 cells upon treatment with CuCH‐NCs/DSF combination (Figure 7A,B).…”

Section: Results and Discussionmentioning

confidence: 99%

A pH‐Activatable Copper‐Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo‐Immunotherapy against Aggressive Cancers

Zhang

Zhu

et al. 2023

Advanced Materials

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Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non‐selective catalysis, low atomic‐utilization efficiency, and undesired off‐target toxicity. Herein, it is reported that peroxidase‐like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH‐NCs) act as a pH‐activatable proenzyme to achieve tumor‐selective and synergistic chemodynamic/chemo‐immunotherapy against aggressive triple‐negative breast cancers (TNBCs). These CuCH‐NCs show pH‐sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)‐mediated reduction into Cu+ species for catalyzing the evolution of H2O2 into hydroxyl radicals (·OH) in a single‐atom‐like manner to cause chemodynamic cell injury, and simultaneously activates non‐toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH‐NCs exhibit considerable tumor‐targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH‐NCs arouse distinct immunogenic cell death effect and upregulate PD‐L1 expression upon disulfiram combination, and thus synergize with anti‐PD‐L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high‐performance proenzymes for synergistic therapy against aggressive cancers.

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Section: Results and Discussionmentioning

confidence: 99%

A pH‐Activatable Copper‐Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo‐Immunotherapy against Aggressive Cancers

Zhang

Zhu

et al. 2023

Advanced Materials

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“…17 Recent clinical studies have revealed that DSF can effectively treat many types of cancer, including lung cancer, 18 melanoma, 19 glioblastoma, 20 and triple-negative breast cancer. 21 The anticancer activity of DSF has been reported to be Cu 2+ dependent, because DSF rapidly metabolizes in vivo to diethyldithiocarbamate (DTC), and DTC chelates rapidly with Cu 2+ to produce a DTC–copper complex (CuET), which are key active ingredients in the anticancer process. 17,22 Various anticancer mechanisms of CuET have been reported, including disrupting the p97-NPL4-UFD1 pathway, inhibiting the ubiquitin–proteasome system and inducing oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy

Li,

Rong,

Wang

et al. 2024

J. Mater. Chem. B

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“…[3][4][5] In a wide range of preclinical studies disulfiram has demonstrated broad anticancer activity across tumor types. 3,[6][7][8][9] Glioblastoma (GB) is the most common and unfortunately also the most malignant of the diffuse gliomas. 10,11 No major breakthrough in systemic treatment has occurred since the introduction of temozolomide.…”

Section: Introductionmentioning

confidence: 99%

“…It is in this context that disulfiram, a drug used to treat alcohol dependency since 1947, has gained increased attention as a potential anticancer drug . In a wide range of preclinical studies disulfiram has demonstrated broad anticancer activity across tumor types …”

Section: Introductionmentioning

confidence: 99%

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Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

et al. 2023

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ImportanceDisulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.ObjectiveTo evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.Design, Setting, and ParticipantsThis was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.InterventionsPatients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).Main Outcomes and MeasuresThe primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.ResultsAmong the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.Conclusions and RelevanceThis randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

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Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Cited by 19 publications

References 54 publications

A pH‐Activatable Copper‐Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo‐Immunotherapy against Aggressive Cancers

A pH‐Activatable Copper‐Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo‐Immunotherapy against Aggressive Cancers

A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

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