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: Hee-Yeon Cho, Weijun Wang, Niyati Jhaveri, Shering Torres, Joshua Tseng, Michelle N Leong, David Jungpa Lee, Amir Goldkorn, Tong Xu, Nicos A Petasis, Stan G Louie, Axel H Schönthal, Florence M Hofman, Thomas C Chen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 11 Pg. 2462-72 (Nov 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22933703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• 2,5-dimethylcelecoxib
• Cytokines
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hspa5 protein, mouse
• Monoterpenes
• Pyrazoles
• Sulfonamides
• perillyl alcohol
• Dacarbazine
• Nelfinavir
• Temozolomide

Topics

• Administration, Intranasal
• Animals
• Brain Neoplasms (blood supply, drug therapy, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytokines (biosynthesis)
• Dacarbazine (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Glioma (blood supply, drug therapy, pathology)
• Humans
• Mice
• Monoterpenes (administration & dosage, chemistry, pharmacology, therapeutic use)
• Nelfinavir (pharmacology)
• Neoplasm Invasiveness
• Neovascularization, Pathologic (drug therapy, pathology)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• Temozolomide
• Xenograft Model Antitumor Assays