Procoagulant Activity of Blood and Microvesicles Is Disturbed by Pneumococcal Pneumolysin, Which Interacts with Coagulation Factors

Oehmcke-Hecht, Sonja; Maletzki, Claudia; Surabhi, Surabhi; Siemens, Nikolai; Khaimov, Valeria; John, Lisa Marie; Peter, Sina Mariella; Hammerschmidt, Sven; Kreikemeyer, Bernd

doi:10.1159/000525479

Cited by 2 publications

(2 citation statements)

References 72 publications

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“…Purification of microvesicles (MVs) was done as described 49 – 52 . Cell culture supernatant was characterized using a NanoSight® LM 10 instrument (Malvern Instruments Ltd., Worcestershire, UK) as described 51 .…”

Section: Methodsmentioning

confidence: 99%

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Kayser,

Wolff,

Berlin

et al. 2024

Sci Rep

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Thromboembolic events are complications in cancer patients and hypercoagulability has been linked to the tissue factor (TF) pathway, making this an attractive target. Here, we investigated the effects of chemotherapeutics and CDK inhibitors (CDKI) abemaciclib/palbociclib (CDK4/6), THZ-1 (CDK7/12/13), and dinaciclib (CDK1/2/5/9) alone and in combination regimens on TF abundance and coagulation. The human colorectal cancer (CRC) cell line HROC173 was treated with 5-FU or gemcitabine to stimulate TF expression. TF+ cells were sorted, recultured, and re-analyzed. The effect of treatment alone or in combination was assessed by functional assays. Low-dose chemotherapy induced a hypercoagulable state and significantly upregulated TF, even after reculture without treatment. Cells exhibited characteristics of epithelial-mesenchymal transition, including high expression of vimentin and mucin. Dinaciclib and THZ-1 also upregulated TF, while abemaciclib and palbociclib downregulated it. Similar results were observed in coagulation assays. The same anticoagulant activity of abemaciclib was seen after incubation with peripheral immune cells from healthy donors and CRC patients. Abemaciclib reversed 5-FU-induced TF upregulation and prolonged clotting times in second-line treatment. Effects were independent of cytotoxicity, senescence, and p27kip1 induction. TF-antibody blocking experiments confirmed the importance of TF in plasma coagulation, with Factor XII playing a minor role. Short-term abemaciclib counteracts 5-FU-induced hypercoagulation and eventually even prevents thromboembolic events.

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Section: Methodsmentioning

confidence: 99%

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Kayser,

Wolff,

Berlin

et al. 2024

Sci Rep

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“…Regarding prothrombotic effects, this has recently been shown not to be true. PLY does not activate platelets to form thrombus, rather it destroys them by forming pores in their membrane [ 45 ] and destroy procoagulant microvesicles impaired coagulation of blood [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

et al. 2023

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Background This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction. Methods The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework. Results Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability. Discussion Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis. Conclusion A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.

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Procoagulant Activity of Blood and Microvesicles Is Disturbed by Pneumococcal Pneumolysin, Which Interacts with Coagulation Factors

Cited by 2 publications

References 72 publications

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Selective but not pan-CDK inhibition abrogates 5-FU-driven tissue factor upregulation in colon cancer

Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

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