Combined inhibition of the cell cycle related proteins Wee1 and Chk1/2 induces synergistic anti-cancer effect in melanoma
| Autor: | Ana Slipicevic, Viola Nähse-Kumpf, Roar Fjær, Karianne G. Fleten, Birgit Engesæter, Elisabeth Emilsen, Gry Irene Magnussen, Vivi Ann Flørenes |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Chk1/2 Cell cycle checkpoint Skin Neoplasms Cancer therapy Caspase 3 Apoptosis Cell Cycle Proteins Pyrimidinones Thiophenes chemistry.chemical_compound Mice Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Genetics Wee1 Animals Humans Urea Mitosis Melanoma Protein Kinase Inhibitors MK1775 Cell Proliferation biology Malignant melanoma Cell growth Nuclear Proteins Drug Synergism Cell Cycle Checkpoints Cell cycle Protein-Tyrosine Kinases medicine.disease AZD7762 Xenograft Model Antitumor Assays Cell biology Checkpoint Kinase 2 Pyrimidines chemistry Oncology biology.protein Cancer research Cell cycle inhibitors Pyrazoles Growth inhibition Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | Background Malignant melanoma has an increasing incidence rate and the metastatic disease is notoriously resistant to standard chemotherapy. Loss of cell cycle checkpoints is frequently found in many cancer types and makes the cells reliant on compensatory mechanisms to control progression. This feature may be exploited in therapy, and kinases involved in checkpoint regulation, such as Wee1 and Chk1/2, have thus become attractive therapeutic targets. Methods In the present study we combined a Wee1 inhibitor (MK1775) with Chk1/2 inhibitor (AZD7762) in malignant melanoma cell lines grown in vitro (2D and 3D cultures) and in xenografts models. Results Our in vitro studies showed that combined inhibition of Wee1 and Chk1/2 synergistically decreased viability and increased apoptosis (cleavage of caspase 3 and PARP), which may be explained by accumulation of DNA-damage (increased expression of γ-H2A.X) - and premature mitosis of S-phase cells. Compared to either inhibitor used as single agents, combined treatment reduced spheroid growth and led to greater tumour growth inhibition in melanoma xenografts. Conclusions These data provide a rationale for further evaluation of the combination of Wee1 and Chk1/2 inhibitors in malignant melanoma. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1474-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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