Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Abstract

Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

Recent Advances of Gold Compounds in Anticancer Immunity

“…Gold compounds exert cytotoxic effects by inhibiting thiol-containing enzymes, especially TrxR (Liu and Gust, 2013 ; Ortego et al, 2014 ; Bian et al, 2019 , 2020a , b ; Fan et al, 2019 ), damaging mitochondrial (Rigobello et al, 2002 ; Rackham et al, 2007 ) and DNA function (Messori et al, 2005 ; Patel et al, 2013 ), all of which may contribute to their clinical anticancer activity. Recently, many groups have found that auranofin, a gold compound widely used in antirheumatic therapy (Sadler and Sue, 1994 ; Shaw, 1999 ), also has anticancer, antibacterial and other properties (Marzano et al, 2007 ; Fiskus et al, 2014 ; Harbut et al, 2015 ; Diez-Martinez et al, 2016 ; Thangamani et al, 2017 ; AbdelKhalek et al, 2019 ; Onodera et al, 2019 ; Raninga et al, 2020 ). Therefore, there is growing interest in the investigation of gold compounds with new applications.…”

RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC

“…Auranofin significantly suppressed NONO and both the STAT3 mRNA and protein expression level in MDA-MB-231 cells (Figure 7 C-E). The murine 4T1.2 syngenic model reflecting TNBC phenotypes 41 and the xenograft model using MDA-MB-231 revealed that NONO expression was decreased by auranofin treatment (Figure 7 F). To next whether the cell growth inhibition by auranofin is dependent on NONO gene expression, we performed a rescue experiment.…”

“…Auranofin is a well-known anti-inflammatory drug used in rheumatoid arthritis 54 . Recently, several studies based on a drug-repositioning concept have suggested that auranofin possesses anti-proliferative effects in cancer cells 41 . Although our current results hint to auranofin being able to modulate NONO activity, other and more specific targeting agents will also need to be explored.…”

“…(C-E) MDA-MB-231 cells were treated with indicated drugs, and the cells were then analyzed by qRT-PCR with the indicated primers (C-D) and WB (E). (F) Western blot analysis of the indicated tumor tissues 41 . (G and H) MDA-MB-231 cells were treated with auranofin, transfected with NONO cDNA, and then analyzed in a CCK8 (G) and colony formation assay (H) .…”

Dihydroartemisinin-Loaded Magnetic Nanoparticles for Enhanced Chemodynamic Therapy

“…In consideration of the high cytotoxicity of MNP-DHA, we tried to use this combination to conduct toxicity experiments on other canonical lethal breast cancer cell lines that were triple negative (MDA-MB-231) and human epidermal growth factor receptor (HER2) overexpressing (MDA-MB-453) (Neve et al, 2006;Lee et al, 2012). Triple-negative breast cancer, defined by the lack of estrogen receptor, progesterone receptor and HER2, frequently developed resistance to chemotherapy over long-term treatment (Kim et al, 2018;Raninga et al, 2020). HER2 was overexpressed in 25-30% of breast cancers which was a considerable proportion, and patients with breast cancers that overexpress HER2 had much lower overall survival and disease-free survival due to high metastasis (Baselga et al, 1998;Slamon et al, 2001;Büyükköroglu et al, 2016).…”