Background:
Dysregulation of the cell cycle is one of the main causes of melanomagenesis. Genome-wide studies showed that
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 WI38 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.
Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
