Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas
Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas
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DOI：
10.1158/1535-7163.mct-12-0321
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发表时间：
2012-11-01
影响因子：
5.7
通讯作者：
Chen, Thomas C.
中科院分区：
文献类型：
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作者：
Cho, Hee-Yeon;Wang, Weijun;Chen, Thomas C.
紫苏醇 (POH) 是一种单萜，已口服用于治疗全身性癌症。然而，当口服使用时，记录了显着的胃肠道副作用和缺乏总体疗效。最近，在巴西一项治疗替莫唑胺 (TMZ) 耐药的恶性神经胶质瘤的 II 期试验中，鼻内给药时 POH 的耐受性良好。本研究探讨 POH 对 TMZ 敏感和 TMZ 耐药的胶质瘤细胞的影响和机制。体外研究表明，POH 对 TMZ 耐药以及 TMZ 敏感的神经胶质瘤细胞具有细胞毒性，并且这种作用与 O-6-甲基鸟嘌呤-DNA 甲基转移酶的表达无关。 POH 部分通过内质网 (ER) 应激途径诱导细胞毒性，如葡萄糖调节蛋白 78 (GRP78)、激活转录因子 3 和 C/EBP 同源蛋白表达增加所示。此外，POH 还阻碍了 mTOR 和 Ras 等生存途径。此外，POH 还降低了敏感和耐药神经胶质瘤细胞的侵袭能力。单独使用 POH 和/或与其他 ER 应激诱导细胞毒性药物（即 2, 5-二甲基塞来昔布、奈非那韦）联合使用可进一步诱导 TMZ 敏感和 TMZ 耐药神经胶质瘤细胞凋亡。为了证明鼻内给药 POH 是否能有效治疗 TMZ 耐药性神经胶质瘤，对患有颅内肿瘤的动物进行鼻内给药 POH。通过鼻内给予 POH 治疗的动物表现出肿瘤生长的减少和存活率的增加。我们的数据表明，当鼻内给药时，POH 是一种有效的抗 TMZ 耐药神经胶质瘤的抗神经胶质瘤细胞毒剂。摩尔癌症治疗； 11（11）； 2462-72。 (c) 2012 年 AACR。
Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O-6-methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally. Mol Cancer Ther; 11(11); 2462-72. (c) 2012 AACR.