Hirakata Camila, Lima Keli, De Almeida Bruna Oliveira, De Miranda Lívia Bassani Lins, Florêncio Katharine Gurgel Dias, Furtado Luciana Costa, Costa-Lotufo Leticia Veras, Machado-Neto João Agostinho
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, CEP 05508-900, Brazil.
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceará, Fortaleza, Ceará, CEP 60440-900, Brazil.
Oncol Lett. 2021 Aug;22(2):610. doi: 10.3892/ol.2021.12871. Epub 2021 Jun 15.
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.
神经胶质瘤是原发性中枢神经系统肿瘤中最常见的类型，尽管在了解该疾病的分子基础方面取得了巨大进展，但新开发的疗法却很少。Reversine是一种合成嘌呤类似物，是一种多激酶抑制剂，可靶向极光激酶A（AURKA）和极光激酶B（AURKB）。在神经胶质瘤中，AURKA或AURKB的高表达与恶性表型和不良预后相关。本研究调查了Reversine在HOG、T98G和U251MG细胞系中相关的细胞和分子抗神经胶质瘤作用。分别通过逆转录定量PCR和蛋白质印迹法评估基因和蛋白质表达。对于功能测定，将人神经胶质瘤细胞系（HOG、T98G和U251MG）暴露于浓度递增的Reversine（0.4-50μM）中，并进行各种细胞和分子测定。Reversine以剂量和/或时间依赖性方式降低了所有神经胶质瘤细胞的活力和克隆形成能力，与U251MG细胞（低AURKA和AURKB表达）相比，HOG（高AURKB表达）和T98G（高AURKA表达）细胞更敏感。值得注意的是，HOG细胞呈现出更高水平的多倍体，而T98G呈现出多个有丝分裂纺锤体，这分别与AURKB和AURKA的主要调节功能一致。在分子测定中，Reversine降低了AURKA和/或AURKB的表达/活性，并增加了DNA损伤和凋亡标志物，但自噬相关蛋白未受到调节。总之，Reversine在神经胶质瘤细胞中有效诱导有丝分裂灾难和凋亡，极光激酶和对DNA损伤有反应的基因的基础水平较高，这可能预示着对该药物的抗神经胶质瘤反应会改善。Reversine可能是抗肿瘤药库中对抗神经胶质瘤的一种潜在新药。
