2. Academic Validation
  3. 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

  • Sci Rep. 2024 May 8;14(1):10582. doi: 10.1038/s41598-024-61076-5.
Annika Kayser # 1,  Annabell Wolff # 1 2,  Peggy Berlin 3,  Lara Duehring 1 2,  Larissa Henze 1 4,  Ralf Mundkowski 5,  Wendy Bergmann 6,  Brigitte Müller-Hilke 6,  Charlotte Wagner 1,  Maja Huehns 7,  Sonja Oehmcke-Hecht # 8,  Claudia Maletzki # 9
Affiliations

Affiliations

  • 1 Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.
  • 2 Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, 18057, Rostock, Germany.
  • 3 Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, 18057, Rostock, Germany.
  • 4 Department of Internal Medicine II, Asklepios Hospital Harz, Goslar, Germany.
  • 5 Center of Pharmacology and Toxicology, Institute of Clinical Pharmacology, Rostock University Medical Center, 18057, Rostock, Germany.
  • 6 Laboratory for Clinical Immunology, Core Facility for Cell Sorting and Cell Analysis, Rostock University Medical Center, 18057, Rostock, Germany.
  • 7 Institute of Pathology, Rostock University Medical Center, 18057, Rostock, Germany.
  • 8 Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, 18057, Rostock, Germany. sonja.oehmcke-hecht@med.uni-rostock.de.
  • 9 Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. claudia.maletzki@med.uni-rostock.de.
  • # Contributed equally.
PMID: 38719932 DOI: 10.1038/s41598-024-61076-5
Abstract

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.

Keywords

Cell sorting; Epithelial-mesenchymal transition; Hypercoagulation; Microvesicles; Senescence; Targeted therapy.

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