The radiosensitizing effect of the aurora kinase inhibitors, ENMD‐2076, on canine mast cell tumours in vitro

Abstract

ENMD-2076 is an aurora kinase inhibitor that also has multi-target tyrosine kinase inhibitor properties. In this study, the mRNA and the protein expression of aurora-A and aurora-B were evaluated in three canine mast cell tumor cell lines. Dose dependent cytotoxicity was seen in the cells treated, and it affected the cell cycle with cells in the G2/M phase being selectively killed. The cells were also evaluated for radiosensitivity with/without ENMD-2076, and radiosensitization was seen after 3 Gy and 6 Gy exposures with ENMD-2076 for 48 hours. Protein expression of caspase-3 was gradually increased, and the expression intensity was highest at 24 hours post irradiation in cells without ENMD-2076 treatment, which indicates that radiation exposure with ENMD-2076 induced cell death faster than radiation treatment alone. Our study results suggest the potential usefulness of treating canine mast cell tumors with aurora kinase inhibitors alone or in conjunction with radiation therapy.

Aurora-A affects radiosenstivity in cervical squamous cell carcinoma and predicts poor prognosis

“…However, the results of another study [ 30 ] were in contrast to those of our study and showed that patients with Aurora-A overexpression had better clinical and histological response to CCRT. In some in vitro studies, inhibition of Aurora-A potently inhibited proliferation of atypical teratoid/rhabdoid tumor cells [ 31 ], glioblastoma neurosphere tumor cells [ 32 ], canine mast cell tumor cells [ 33 ] and sensitized these cells to radiation. In both in vitro and in vivo models of human cancers, including hepatocellular carcinoma[ 34 ], androgen-insensitive prostate cancer [ 35 ], oral squamous cell carcinoma [ 36 ] and lung cancer [ 37 ], some novel small molecule Aurora-A inhibitors showed radiation sensitization.…”

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

“…ENMD-2076 (EntreMed) has a 25-fold better selectivity for AURKA over AURKB, and an IC50 of 14 nM [135], although an inhibitory activity towards multiple kinases has been described for this compound [135]. In vitro experiments revealed that ENMD-2076 induces a G2/M checkpoint block and cell death, alone or in combination with radiosensitisation [136]. Phase I trials showed that ENMD-2076 is a lowcytotoxicity compound in patients affected with relapsed or refractory acute myeloid leukaemia, or chronic myelomonocytic leukaemia [137].…”

Aurora-A Induces Chemoresistance Through Activation of the AKT/mTOR Pathway in Endometrial Cancer

“…As soon as a strong link between Aurora-A and cancer was found, many pharmaceutical companies quickly started trying to develop Aurora-A inhibitors for cancer treatment. Inhibitors of Aurora kinases, such as MLN8237 (8), MK-5108 (9), and ENMD-2076 (10), have been developed but none have yet gone beyond Phase III trials (5), suggesting the functions of Aurora-A have not been fully understood in cancer cells. More importantly, in a complex organism, Aurora-A is an oncogene in mammary epithelium and glands (11, 12), whereas it could be a tumor suppressor in neural stem cells (13), so it should be considered that Aurora-A has cell type-specific functions.…”