Enhanced anti-tumor effect of zoledronic acid combined with temozolomide against human malignant glioma cell expressing O6-methylguanine DNA methyltransferase.
Enhanced anti-tumor effect of zoledronic acid combined with temozolomide against human malignant glioma cell expressing O6-methylguanine DNA methyltransferase.
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DOI：
10.1371/journal.pone.0104538
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Nakao N
中科院分区：
文献类型：
--
作者：
Fukai J;Koizumi F;Nakao N
替莫唑胺（TMZ）是一种DNA甲基化剂，广泛用于恶性胶质瘤的辅助治疗。 O6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 是一种 DNA 修复酶，经常被认为是限制 TMZ 功效的主要因素。唑来膦酸（ZOL）在临床上用于治疗癌症引起的骨疾病，通过抑制甲羟戊酸途径和细胞内小G蛋白的异戊二烯化来诱导细胞凋亡，似乎具有直接抗肿瘤活性。在本研究中，我们评估了 ZOL 是否可以在表达 MGMT 的人类恶性胶质瘤细胞中有效用作 TMZ 的佐剂。检测到 MGMT 表达的恶性神经胶质瘤细胞系即使在较长时间暴露下也没有表现出 TMZ 的生长抑制作用。然而，TMZ与ZOL的组合实验表明，超加和效应导致细胞生长显着下降。在 TMZ/ZOL 联合治疗中，与每次单次药物暴露相比，细胞凋亡率明显增加，并且观察到 caspase-3 的显着激活和聚（ADP-核糖）聚合酶的裂解。 ZOL 处理的细胞中 Ras-GTP、MAPK 和 Akt 磷酸化以及 MGMT 表达量下降。皮下异种移植模型显示联合 TMZ/ZOL 治疗后肿瘤生长显着减少。这些结果表明，ZOL 有效抑制恶性胶质瘤细胞中 Ras 的活性，并增强 TMZ 介导的细胞毒性，诱导表达 MGMT 并对 TMZ 耐药的恶性胶质瘤细胞生长抑制和凋亡。基于这项工作，TMZ 与 ZOL 的组合可能是恶性胶质瘤的一种潜在疗法，由于细胞耐药性，TMZ 的治疗效果较差。
Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance.
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影响因子：
11.2
作者：
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通讯作者：
Holland, EC
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