Perillyl alcohol for the treatment of temozolomide-resistant gliomas
| Autor: | Hee-Yeon Cho, Stan G. Louie, Thomas C. Chen, Amir Goldkorn, Weijun Wang, Niyati Jhaveri, Shering Torres, Axel H. Schönthal, Nicos A. Petasis, Tong Xu, Michelle N. Leong, David Jungpa Lee, Florence M. Hofman, Joshua Tseng |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Methyltransferase chemistry.chemical_compound Mice Glioma Cell Line Tumor medicine Temozolomide Cytotoxic T cell Animals Humans Neoplasm Invasiveness Endoplasmic Reticulum Chaperone BiP PI3K/AKT/mTOR pathway Administration Intranasal Cell Proliferation Sulfonamides Nelfinavir Cell Death Neovascularization Pathologic business.industry Brain Neoplasms Perillyl alcohol medicine.disease Endoplasmic Reticulum Stress Xenograft Model Antitumor Assays Dacarbazine Oncology chemistry Apoptosis Drug Resistance Neoplasm Cancer research Monoterpenes Cytokines Pyrazoles Nasal administration business medicine.drug |
| Zdroj: | Molecular cancer therapeutics. 11(11) |
| ISSN: | 1538-8514 |
| Popis: | 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 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. ©2012 AACR. |
| Databáze: | OpenAIRE |
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