Departments of Neurosurgery and Pathology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Mol Cancer Ther. 2012 Nov;11(11):2462-72. doi: 10.1158/1535-7163.MCT-12-0321. Epub 2012 Aug 28.
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.
薄荷醇（POH）是一种单萜，已被口服用于治疗全身性癌症。然而，当口服使用时，记录到明显的胃肠道副作用和缺乏整体疗效。最近，在巴西进行的一项用于治疗替莫唑胺（TMZ）耐药恶性神经胶质瘤的 II 期试验中，经鼻内给予 POH 时耐受性良好。本研究探讨了 POH 对 TMZ 敏感和 TMZ 耐药神经胶质瘤细胞的作用和机制。体外研究表明，POH 对 TMZ 耐药和 TMZ 敏感的神经胶质瘤细胞均具有细胞毒性作用，并且这种作用与 O（6）-甲基鸟嘌呤-DNA 甲基转移酶表达无关。POH 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 同源蛋白的表达增加。此外，POH 抑制了生存途径，如 mTOR 和 Ras。同样，POH 降低了敏感和耐药神经胶质瘤细胞的侵袭能力。POH 单独或与其他诱导 ER 应激的细胞毒性药物（即 2,5-二甲基-celecoxib、奈非那韦）联合使用，进一步诱导 TMZ 敏感和 TMZ 耐药神经胶质瘤细胞凋亡。为了证明经鼻内给予 POH 是否对治疗 TMZ 耐药神经胶质瘤有效，将颅内肿瘤动物给予 POH 经鼻内给药。通过经鼻内给予 POH 治疗的动物表现出肿瘤生长减少和存活时间增加。我们的数据表明，当经鼻内给予时，POH 是一种有效的 TMZ 耐药神经胶质瘤的抗神经胶质瘤细胞毒性剂。
