Perillyl Alcohol (POH) For the Treatment of Temozolomide-Resistant Gliomas
Menée in vitro et in vivo, cette étude évalue l'efficacité de l'alcool de périllyle, administré par voie nasale, pour le traitement d'un gliome résistant au temozolomide
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 O6-methylguanine-DNA methyltransferase (MGMT) 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 (ATF3), and C/EBP-homologous protein (CHOP). 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 demonstrate 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 demonstrate that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally.
http://mct.aacrjournals.org/content/early/2012/08/28/1535-7163.MCT-12-0321.abstract