The Evaluation of Effect of Aurora Kinase Inhibitor CCT137690 in Melanoma and Melanoma Cancer Stem Cell
| Autor: | Cigir Biray Avci, Fatma Sogutlu, Cagla Kayabasi, Sunde Yilmaz Susluer, Besra Ozmen Yelken, Sezgi Kipcak, Aycan Asik, Roya Gasimli, Cumhur Gündüz |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Identification Cell cycle checkpoint Cell Survival Pyridines Overexpression Cell Aurora inhibitor Antineoplastic Agents Expression Apoptosis Melanoma cancer stem cell Polyploidy Structure-Activity Relationship aurora kinase inhibitor mitotic slippage medicine Tumor Cells Cultured melanoma Cytotoxic T cell Humans Clonogenic assay Protein Kinase Inhibitors Aurora Kinase A Cell Proliferation Pharmacology Dose-Response Relationship Drug Targets Melanoma Imidazoles Cell cycle medicine.disease medicine.anatomical_structure Cancer research Molecular Medicine Stem cell Drug Screening Assays Antitumor CCT137690 |
| Popis: | Background: Dysregulation of the cell cycle is one of the main causes of melanomagenesis. Genomewide studies showed that the expression of Aurora -A and -B significantly has been upregulated in melanoma. However, there is no FDA approved drug targeting aurora kinases in the treatment of melanoma. In addition, the development of resistance to chemotherapeutic agents in the treatment of melanoma and, as a result, the relapse due to heterogeneous cell groups in patients is a second phenomenon that causes treatment failure. Therefore, there is an urgent need for therapeutic alternatives targeting both melanoma and Melanoma Cancer Stem Cells (MCSCs) in treatments. At this stage, cell cycle regulators become promising targets. Objective: In this study, we aimed to identify the effects of Aurora kinase inhibitor CCT137690 on the cytotoxicity, apoptosis, cell cycle, migration, and colony formation and expression changes of genes related to proliferation, cell death and cell cycle in melanoma and melanoma cancer stem cell. In addition, we investigated the apoptotic and cytostatic effects of CCT137690 in normal fibroblast cells. Methods: We evaluated the cytotoxic effect of CCT137690 in MCSCs, NM2C5 referring as melanoma model cells and WI-38 cells by using the WST-1 test. The effect of CCT137690 on apoptosis was detected via Annexin V and JC-1 method; on cell cycle progression by cell cycle test; on gene expression by using RT-PCR, on migration activity by wound healing assay and clonal growth by clonogenic assay in NM2C5 cells and MCSCs. The effects of CCT137690 in WI-38, referring as healthy fibroblast cell, were assessed through Annexin V and cell cycle method. Results: CCT137690 was determined to have a cytotoxic and apoptotic effect in MCSCs and melanoma. It caused polyploidy and cell cycle arrest at the G2/M phase in MCSCs and melanoma cells. The significant decrease in the expression of MMP2, MMP7, MMP10, CCNB1, IRAK1, PLK2 genes, and the increase in the expression of PTEN, CASP7, p53 genes were detected. Conclusion: Aurora kinases inhibitor CCT137690 displays promising anticancer activity in melanoma and especially melanoma cancer stem cells. The effect of CCT137690 on melanoma and MCSC may provide a new approach to treatment protocols. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|