Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts

Beckmann, Lennart; Rolling, Christina C.; Voigtländer, Minna; Mäder, Jonathan; Klingler, Felix; Schulenkorf, Anita; Lehr, Carina; Bokemeyer, Carsten; Ruf, Wolfram

doi:10.3390/cancers13163941

Cited by 11 publications

(6 citation statements)

References 75 publications

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“…Our previous work has demonstrated that circulating PDI is associated with increased risks of cancer‐induced thrombosis, 9 along with increased levels of tissue factor 47 . Interestingly, tissue factor is also expressed on the surface of some cancer cells 48 and in this study, we found that both cellular thiol isomerase activity (Figure 2A) and tissue factor‐dependent Factor Xa generation (Figure 4E) was inhibited by zafirlukast in ovarian cancer cells, which would further support exploration of zafirlukast for cancer‐induced thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

et al. 2023

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Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC 50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian How to cite this article: Gelzinis JA, Szahaj MK, Bekendam RH, et al. Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic.

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Section: Discussionmentioning

confidence: 99%

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

et al. 2023

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“…Bacitracin and quercetin-3-rutinoside (rutin) are two PDI inhibitors. A recent study showed that bacitracin and rutin inhibited LPS induction of TF protein expression and activity in CD14-positive human monocytes and human peripheral blood mononuclear cells (PBMCs), respectively 88 . In addition, rutin reduced LPS induction of TF mRNA in human PBMCs.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Monocyte Tissue Factor Expression: Lipopolysaccharide Induction and Roles in Pathological Activation of Coagulation

Sachetto

Mackman

2023

Thromb Haemost

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The coagulation system is a part of the mammalian host defense system. Pathogens and pathogen components, such as bacterial lipopolysaccharide (LPS), induce tissue factor (TF) expression in circulating monocytes that then activates the coagulation protease cascade. Formation of a clot limits dissemination of pathogens, enhances the recruitment of immune cells and facilitates killing of pathogens. However, excessive activation of coagulation can lead to thrombosis. Here, we review studies on the mechanism of LPS induction of TF expression in monocytes and its contribution to thrombosis and disseminated intravascular coagulation. Binding of LPS to Toll-like receptor 4 on monocytes induces a transient TF expression that involves activation of intracellular signaling pathways and binding of various transcription factors, such as c-rel/p65 and c-Fos/c-Jun, to the TF promoter. Inhibition of TF in endotoxemia and sepsis models reduces activation of coagulation and improves survival. Studies with endotoxemic mice showed that hematopoietic cells and myeloid cells play major roles in the activation of coagulation. Monocyte TF expression is also increased after surgery. Activated monocytes release TF-positive extracellular vesicles (EVs) and levels of circulating TF-positive EVs are increased in endotoxemic mice and in patients with sepsis. More recently, it was shown that inflammasomes contribute to the induction of TF expression and activation of coagulation in endotoxemic mice. Taken together, these studies indicate that monocyte TF plays a major role in the LPS-induced activation of coagulation. Selective inhibition of monocyte TF expression may reduce pathologic activation of coagulation in sepsis and other diseases.

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“…2A ), as assessed by a previously described chromogenic Xa generation endpoint assay. 9 High dosages of argatroban were required to maintain the activated partial thromboplastin time within the upper therapeutic target range ( Fig. 2B ).…”

Section: Case Presentationmentioning

confidence: 99%

Expression and Release of Tumor Cell Tissue Factor Triggers Recurrent Thromboembolism in a Patient with Endometrial Cancer

et al. 2023

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Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19–9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.

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Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts

Cited by 11 publications

References 75 publications

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

Monocyte Tissue Factor Expression: Lipopolysaccharide Induction and Roles in Pathological Activation of Coagulation

Expression and Release of Tumor Cell Tissue Factor Triggers Recurrent Thromboembolism in a Patient with Endometrial Cancer

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