Xu Wei, Hu Jiamei, Liu Weiwei, Zhu Qiong, Gong Xuan, Zhu Pengpeng, Yang Xiao, Xia Rui, Xue Rui
Department of Anesthesiology, The First People's Hospital of Jingzhou, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China.
Department of Obstetrics, The Third People's Hospital of Jingzhou, Jingzhou, Hubei, China.
IUBMB Life. 2021 Feb;73(2):341-348. doi: 10.1002/iub.2433. Epub 2020 Dec 24.
Glioma alone accounts for 30% of various kinds of primary brain tumors and is the highest cause of mortality associated with intracranial malignant cancers. In the present study, Suzuki-coupling products of remimazolan were synthesized and investigated for anti-neoplastic property against glioma cells. RFMSP treatment for 48 hr suppressed viabilities of U-118MG and U87MG cells in dose dependent manner. Exposure of primary astrocytes to RFMSP at 2-20 μM concentration range minimally affected viabilities. RFMSP treatment at 5 μM doses raised apoptotic cell count to 53.8 ± 2.3% and 48.2 ± 1.8%, respectively in U-118MG and U87MG cells. Treatment of the cells with RFMSP induced nuclear condensation and subsequent fragmentation. In RFMSP treated U-118MG and U87MG cells, NF-κB p65 expression was markedly suppressed compared to the control cells. Additionally, RFMSP treatment decreased the ratio of nuclear to total NF-κB p65 level in both the cell lines. Treatment of U-118MG and U87MG cells with 5 μM RFMSP for 48 hr caused a marked down-regulation in survivin and XIAP levels. Treatment with RFMSP promoted Bax expression and suppressed Bcl-2 level. The caspase-9 and -3 activation was markedly induced by RFMSP treatment in U-118MG and U87MG cells compared to the control cells. In summary, the RFMSP synthesized by Suzuki-coupling of RFMSP inhibited glioma cell survival via DNA damage mediated apoptosis. The anti-glioma potential of RFMSP involved down-regulation of NF-κB expression, targeted survivin & XIAP levels and induced caspase activation in glioma cells. Therefore, RFMSP may be studied further as therapeutic agent for the treatment of glioma.
仅神经胶质瘤就占各种原发性脑肿瘤的30%，是颅内恶性肿瘤相关死亡率最高的原因。在本研究中，合成了瑞米马唑仑的铃木偶联产物，并研究了其对神经胶质瘤细胞的抗肿瘤特性。RFMSP处理48小时以剂量依赖性方式抑制U-118MG和U87MG细胞的活力。在2-20μM浓度范围内，将原代星形胶质细胞暴露于RFMSP对其活力的影响最小。5μM剂量的RFMSP处理分别使U-118MG和U87MG细胞中的凋亡细胞计数提高到53.8±2.3%和48.2±1.8%。用RFMSP处理细胞诱导细胞核浓缩并随后碎片化。在RFMSP处理的U-118MG和U87MG细胞中，与对照细胞相比，NF-κB p65表达明显受到抑制。此外，RFMSP处理降低了两种细胞系中细胞核与总NF-κB p65水平的比率。用5μM RFMSP处理U-118MG和U87MG细胞48小时导致存活素和XIAP水平明显下调。用RFMSP处理促进了Bax表达并抑制了Bcl-2水平。与对照细胞相比，RFMSP处理在U-118MG和U87MG细胞中明显诱导了caspase-9和-3的激活。总之，通过RFMSP的铃木偶联合成的RFMSP通过DNA损伤介导的凋亡抑制神经胶质瘤细胞存活。RFMSP的抗神经胶质瘤潜力涉及NF-κB表达的下调、靶向存活素和XIAP水平以及诱导神经胶质瘤细胞中的caspase激活。因此，RFMSP可作为治疗神经胶质瘤的治疗剂进行进一步研究。
