Introduction: Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. Due to significant gastrointestinal side effects and lack of overall efficacy, this agent was not used as an oral anti-cancer agent. Recently, POH was administered intranasally in a Phase II trial for the treatment of recurrent malignant gliomas, with 50% progression free survival (PFS) for 6 months. The present study further explores the effects and mechanisms of POH on temozolomide (TMZ) sensitive and resistant glioma cells in vitro and in vivo.
Methods: Measurements of Endoplasmic Reticulum (ER)was determined by western blots of ERS markers. Invasion assay performed using Boyden chambers. Intranasal delivery of POH was conducted in nude mice.
Results: POH induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. This agent induces cytotoxicity via 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). Combination with other ERS inducing agents ie 2,5-dimethyl-celecoxib (DMC) or nelfinavir (NFV) accentuated this effect. POH also decreased the invasive capacity of sensitive and resistant glioma cells. To demonstrate whether intranasal delivery of POH is effective in treating gliomas, animals bearing intracranial tumors were treated intranasally with POH. Luciferase- positive U251 TMZ-resistant glioma cells were stereotactically implanted into the right frontal lobe of nude mice. The intranasal delivery of POH had no toxicity, and demonstrated a decrease in tumor growth,increase in survival, and increased GRP78 in tumor tissue.
Conclusions: Our data demonstrate that POH is an effective anti-glioma agent for recurrent temozolomide resistant gliomas which can be administered intranasally. A purified GMP quality POH has been prepared, and is now in the process of obtaining IND approval for a Phase I/IIa clinical trial for recurrent GBM
Patient Care: new treatment methodology
Learning Objectives: learn concept of intranasal delivery for gliomas, concept of endoplasmic reticulum stress