title: Perillyl alcohol for the treatment of temozolomide-resistant gliomas.
abstract: 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.
authors.affiliation: Departments of Neurosurgery and Pathology, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Hee-Yeon
authors.initials: HY
authors.lastname: Cho
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.forename: Niyati
authors.initials: N
authors.lastname: Jhaveri
authors.forename: Shering
authors.initials: S
authors.lastname: Torres
authors.forename: Joshua
authors.initials: J
authors.lastname: Tseng
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Leong
authors.forename: David Jungpa
authors.initials: DJ
authors.lastname: Lee
authors.forename: Amir
authors.initials: A
authors.lastname: Goldkorn
authors.forename: Tong
authors.initials: T
authors.lastname: Xu
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Stan G
authors.initials: SG
authors.lastname: Louie
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D039821:Monoterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019888:Nelfinavir / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: C506698:2,5-dimethylcelecoxib; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D039821:Monoterpenes; D011720:Pyrazoles; D013449:Sulfonamides; C032208:perillyl alcohol; D003606:Dacarbazine; D019888:Nelfinavir; D000077204:Temozolomide