Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells
| Autor: | Yao Lin, A. Robertson, Duncan I. Jodrell, Jo L. Bramhall, Jennifer Harrington, Daniella Zheleva, Tashinga E. Bapiro, Frances M. Richards, B-F Krippendorff |
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| Přispěvatelé: | Richards, Fran [0000-0001-7947-7853], Jodrell, Duncan [0000-0001-9360-1670], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Paclitaxel pancreatic cancer Bone Marrow Cells Pharmacology Protein Serine-Threonine Kinases Granulocyte-Macrophage Progenitor Cells chemistry.chemical_compound Aurora Kinases Precursor cell Pancreatic cancer Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Medicine Humans Protein Kinase Inhibitors Aurora Kinase A Protein-Serine-Threonine Kinases business.industry Stem Cells Drug Synergism medicine.disease Pancreatic Neoplasms medicine.anatomical_structure Oncology chemistry embryonic structures Cancer research combination treatment Bone marrow biological phenomena cell phenomena and immunity Stem cell business Translational Therapeutics CYC3 mitotic inhibitor |
| Zdroj: | British Journal of Cancer |
| DOI: | 10.17863/cam.49154 |
| Popis: | BACKGROUND: Amplification of aurora kinase A (AK-A) overrides the mitotic spindle assembly checkpoint, inducing resistance to taxanes. RNA interference targeting AK-A in human pancreatic cancer cell lines enhanced taxane chemosensitivity. In this study, a novel AK-A inhibitor, CYC3, was investigated in pancreatic cancer cell lines, in combination with paclitaxel. METHODS: Western blot, flow cytometry and immunostaining were used to investigate the specificity of CYC3. Sulforhodamine B staining, time-lapse microscopy and colony-formation assays were employed to evaluate the cytotoxic effect of CYC3 and paclitaxel. Human colony-forming unit of granulocyte and macrophage (CFU-GM) cells were used to compare the effect in tumour and normal tissue. RESULTS: CYC3 was shown to be a specific AK-A inhibitor. Three nanomolar paclitaxel (growth inhibition 50% (GI(50)) 3 nM in PANC-1, 5.1 nM in MIA PaCa-2) in combination with 1 μM CYC3 (GI(50) 1.1 μM in MIA PaCa2 and 2 μM in PANC-1) was synergistic in inhibiting pancreatic cell growth and causing mitotic arrest, achieving similar effects to 10-fold higher concentrations of paclitaxel (30 nM). In CFU-GM cells, the effect of the combination was simply additive, displaying significantly less myelotoxicity compared with high concentrations of paclitaxel (30 nM; 60-70% vs 100% inhibition). CONCLUSION: The combination of lower doses of paclitaxel and CYC3 merits further investigation with the potential for an improved therapeutic index in vivo. |
| Databáze: | OpenAIRE |
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