Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI-H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation. TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI-H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA. Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).

Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer.

This article reviews the biologic effects of cyclophosphamide and azathioprine relevant to the treatment of systemic lupus erythematosus (SLE). Other agents used less commonly for SLE, such as methotrexate, chlorambucil, and cyclosporin-A, receive more limited attention. Clinical studies of efficacy and toxicity of these agents in their treatment of SLE are then described in detail.

Immunosuppressive drug therapy of systemic lupus erythematosus

The gold complexes.

Cytotoxic drugs are often combined with glucocorticoids in the therapy of immune-mediated diseases. Cyclophosphamide, azathioprine, chlorambucil, and methotrexate are cytotoxic drugs used most commonly for the purpose of immunosuppression. Cyclophosphamide and chlorambucil are alkylating agents, which cause cross-linking of DNA resulting in altered protein production, decreased cell division, and cell death. Azathioprine and methotrexate are anti-metabolites, which cause inhibition of DNA synthesis and a cascade of other effects. These drugs, in general, are more effective if administered during the initial phases of disease when immunocompetent lymphocytes are in a phase of rapid proliferation. This is often impractical in the clinical situation and may explain therapeutic failures. This article focuses on the use of these drugs in the treatment of immune-mediated diseases in dogs and cats and covers mechanisms of action, dosages, and side effects of individual cytotoxic agents.

The use of cytotoxic agents in the treatment of immune-mediated diseases of dogs and cats.

Pharmacology of antiarthritic drugs.

Natural Killer (NK) cell activity was measured in 80 patients with rheumatoid arthritis (RA) grouped according to medication into 1) controls not in remission-inducing therapy, 2) patients treated with oral gold (auranofin), 3) parenteral gold (sodium aurothiomalate) and 4) azathioprine. Baseline, interferon (IF)-enhanced and interleukin 2 (Il-2)-enhanced NK cell activity of patients in the two gold groups did not differ from that of controls, while NK cell activity before and after exposure to IF and Il-2 was significantly suppressed in patients on azathioprine (p less than 0.01). The percentage of Large Granular Lymphocytes did not differ in the four groups while the percentage of Leu 11 positive cells and the total number of lymphocytes were significantly lower in the azathioprine group. Sixty out of 80 patients received nonsteroidal anti-inflammatory drugs (NSAID), whereas 20 did not. A comparison of these two groups showed no influence of NSAID on NK cell activity.

The in vivo effect of triethylphosphine gold (auranofin), sodium aurothiomalate and azathioprine on natural killer cell activity of patients with rheumatoid arthritis.

The percentages of CD5+ (pan T), CD8+ (mainly T suppressor) and CD4+ (mainly T helper) cells were studied in 80 patients with rheumatoid arthritis (RA), grouped according to medication into four groups: 1) controls, not receiving remission-inducing therapy, 2) patients on oral gold (triethylphosphine gold, auranofin), 3) patients on parenteral gold (sodium aurothiomalate) and 4) patients on azathioprine. The total number of lymphocytes was not influenced by treatment with auranofin or sodium aurothiomalate, while the number of lymphocytes was depressed in the azathioprine-treated group (P less than 0.01). Neither treatment with azathioprine or parenteral gold, nor treatment with azathioprine influenced the CD4+/CD8+ ratio.

The in vivo effect of triethylphosphine gold (auranofin), sodium aurothiomalate and azathioprine on lymphocyte subsets of patients with rheumatoid arthritis.

Pharmacological concentrations of auranofin (oral gold) modulated NK cell activity in a dose dependent biphasic manner. In vitro low doses enhanced NK cell activity, while high doses inhibited the NK cell activity. Sodium aurothiomalate (parenteral gold) had no effect. The effect of auranofin on NK cell function was irreversible and independent of the presence of monocytes. Neither IF nor Il-2 abolished the auranofin-suppressed NK cell activity. When NK cell activity was enhanced by low doses of auranofin, both IF and Il-2 could further boost the NK cell function. Using percoll fractionated NK cell enriched populations in a single cell agarose assays, it was shown that auranofin did not influence effector/target cell conjugate formation. The effect of auranofin on NK cell activity is thus due to an influence on the lytic step.

Characterization of the in vitro effect of triethylphosphine gold (auranofin) on human NK cell activity.

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The in vivo effect of triethylphosphine gold (auranofin), sodium aurothiomalate and azathioprine on natural killer cell activity of patients with rheumatoid arthritis.

The in vivo effect of triethylphosphine gold (auranofin), sodium aurothiomalate and azathioprine on lymphocyte subsets of patients with rheumatoid arthritis.

Characterization of the in vitro effect of triethylphosphine gold (auranofin) on human NK cell activity.