The Evaluation of Effect of Aurora Kinase Inhibitor CCT137690 in Melanoma and Melanoma Cancer Stem Cell

Abstract

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.

Computational and Biophysical Characterization of Heterocyclic Derivatives of Anthraquinone against Human Aurora Kinase A

“…The AurA gene itself is revealed to be amplified in >50 and >12% of primary colorectal and breast tumors, respectively, as well as in prostate, colon, ovarian, and cervical tumor cells. − The translated protein has also been observed to overexpress, resulting in elevated kinase activity in several tumor types. , In cancerous cells, the AurA protein has been known to overexpress and localize mutually in the nucleus as well as in the cytoplasm, irrespective of their cell-cycle phases . The interactions between AurA and tumor suppressor p53 have frequently been linked to uncontrolled cell growth, while its inhibition through modulatory compounds has been postulated to trigger the activity of p53, which further leads to proliferation arrest and senescence in melanoma cells. − Overexpression of AurA has also been documented to increase genomic instability and aneuploidy by interrupting cell-cycle checkpoints while supporting cancer cell endurance and chemoresistance by activating the PI3K/Akt/GSK3 signaling cascade. ,, Hence, modulation of AurA activity has been deemed an essential approach to effective anticancer therapy.…”

“… 17 The interactions between AurA and tumor suppressor p53 have frequently been linked to uncontrolled cell growth, while its inhibition through modulatory compounds has been postulated to trigger the activity of p53, which further leads to proliferation arrest and senescence in melanoma cells. 18 − 20 Overexpression of AurA has also been documented to increase genomic instability and aneuploidy by interrupting cell-cycle checkpoints while supporting cancer cell endurance and chemoresistance by activating the PI3K/Akt/GSK3 signaling cascade. 8 , 21 , 22 Hence, modulation of AurA activity has been deemed an essential approach to effective anticancer therapy.…”