Targeting glioma cells by antineoplastic activity of reversine

Abstract

Gliomas are the most common type of primary central nervous system tumors and despite great advances in understanding the molecular basis of the disease very few new therapies have been developed. Reversine, a synthetic purine analog, is a multikinase inhibitor that targets aurora kinase A (AURKA) and aurora kinase B (AURKB). In gliomas, a high expression of AURKA or AURKB is associated with a malignant phenotype and a poor prognosis. The present study investigated reversine-related cellular and molecular antiglioma effects in HOG, T98G and U251MG cell lines. Gene and protein expression were assessed by reverse transcription-quantitative PCR and western blotting, respectively. For functional assays, human glioma cell lines (HOG, T98G and U251MG) were exposed to increasing concentrations of reversine (0.4–50 µM) and subjected to various cellular and molecular assays. Reversine reduced the viability and clonogenicity in a dose- and/or time-dependent manner in all glioma cells, with HOG (high AURKB-expression) and T98G (high AURKA-expression) cells being more sensitive compared with U251MG cells (low AURKA- and AURKB-expression). Notably, HOG cells presented higher levels of polyploidy, while T98G presented multiple mitotic spindles, which is consistent with the main regulatory functions of AURKB and AURKA, respectively. In molecular assays, reversine reduced AURKA and/or AURKB expression/activity and increased DNA damage and apoptosis markers, but autophagy-related proteins were not modulated. In conclusion, reversine potently induced mitotic catastrophe and apoptosis in glioma cells and higher basal levels of aurora kinases and genes responsive to DNA damage and may predict improved antiglioma responses to the drug. Reversine may be a potential novel drug in the antineoplastic arsenal against gliomas.

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

“…In mouse, reversine-treated embryos upregulate the senescent markers p53 and p21 13 and thus fail to give rise to viable embryos 12 . Our results indicate that reversine also downregulates PARP1, as previously observed in glioma 60 . Thus, the effect of reversine on embryo development can be due to a combination of increase in DNA damage and downregulation of DNA repair.…”

“…Reversine-treated mouse embryos upregulate the senescent markers p53 and p21 (Singla et al, 2020) and fail to give rise to viable embryos (Bolton et al, 2016). Our results further indicate that reversine downregulates PARP1, as previously observed in glioma (Hirakata et al, 2021). Thus, reversine treatment may compromise embryo development due to a combined increase in DNA damage and decrease in DNA repair.…”

Brain Regeneration Resembles Brain Cancer at Its Early Wound Healing Stage and Diverges From Cancer Later at Its Proliferation and Differentiation Stages

“…For example, Camk2 genes have been found to be strongly downregulated in GBM compared to the normal brain tissue (Johansson et al, 2005;Xiong et al, 2019;He and Li, 2021). Shc3 and kras are likewise downregulated in primary cultures and patient samples of GBM, while shc1, gadd45a and tgfbr2 are strongly upregulated (Magrassi et al, 2005;Lymbouridou et al, 2009;Guo et al, 2018;Hirakata et al, 2021). Moreover, the tumor suppressors pten and tp53 are frequently mutated and non-functional in GBM (Benitez et al, 2017;Zhang et al, 2018).…”

Reversine inhibits proliferation and induces apoptosis of human osteosarcoma cells through targeting MEK1

“…The double features of dedifferentiative and anti-tumor for reversine could be rationalized by its distinctive mechanism of action [9] , [10] . Recent studies have demonstrated that reversine can induce polyploidy, cell apoptosis and autophagy, and inhibit cell proliferation, invasion and metastasis, and it also exhibited significant cytotoxic effect on a variety of tumor cell lines in vitro [11] , [12] , [13] .…”