دورية أكاديمية
أعرض في EDS

Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division.

التفاصيل البيبلوغرافية
العنوان: Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division.
المؤلفون: Maia ARR; Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Linder S; Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Song JY; Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Vaarting C; Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Boon U; Division of Molecular Pathology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Pritchard CEJ; Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Velds A; Genomics Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Huijbers IJ; Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., van Tellingen O; Laboratory of Clinical Chemistry and Hematology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Jonkers J; Division of Molecular Pathology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands., Medema RH; Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands. r.medema@nki.nl.
المصدر: British journal of cancer [Br J Cancer] 2018 Jun; Vol. 118 (12), pp. 1586-1595. Date of Electronic Publication: 2018 May 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.
مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*pharmacology , Cell Cycle Proteins/*antagonists & inhibitors , Docetaxel/*pharmacology , Neoplasms/*drug therapy , Paclitaxel/*pharmacology , Protein Kinase Inhibitors/*pharmacology , Protein Serine-Threonine Kinases/*antagonists & inhibitors , Protein-Tyrosine Kinases/*antagonists & inhibitors, Animals ; BRCA1 Protein/deficiency ; BRCA1 Protein/genetics ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Docetaxel/administration & dosage ; Drug Synergism ; Female ; Humans ; MCF-7 Cells ; Mice ; Mitosis/drug effects ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/pathology ; Paclitaxel/administration & dosage ; Protein Kinase Inhibitors/administration & dosage ; Tumor Suppressor Protein p53/deficiency ; Tumor Suppressor Protein p53/genetics ; Xenograft Model Antitumor Assays
مستخلص: Background: Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice.
Methods: To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1 -/- ;TP53 -/- mammary tumours with docetaxel and/or Cpd-5. The tumours were analysed regarding their histopathology, chromosome segregation errors, copy number variations and cell death to understand the mechanism of action of the drug combination.
Results: The enhanced efficacy of combining an Mps1 inhibitor with clinically relevant doses of docetaxel is associated with an increase in multipolar anaphases, aberrant nuclear morphologies and cell death. Tumours treated with docetaxel and Cpd-5 displayed more genomic deviations, indicating that chromosome stability is affected mostly in the combinatorial treatment.
Conclusions: Our study shows that the synergy between taxanes and Mps1 inhibitors depends on increased errors in cell division, allowing further optimisation of this treatment regimen for cancer therapy.
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المشرفين على المادة: 0 (BRCA1 Protein)
0 (BRCA1 protein, human)
0 (Cell Cycle Proteins)
0 (Protein Kinase Inhibitors)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
15H5577CQD (Docetaxel)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.12.1 (TTK protein, human)
P88XT4IS4D (Paclitaxel)
تواريخ الأحداث: Date Created: 20180509 Date Completed: 20190716 Latest Revision: 20211204
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6008333
DOI: 10.1038/s41416-018-0081-2
PMID: 29736010
قاعدة البيانات: MEDLINE
الوصف
تدمد:1532-1827
DOI:10.1038/s41416-018-0081-2