Perillyl Alcohol: A Pharmacotherapeutic Report

Abstract

Tumors of glial origins such as glioblastoma multiforme (GBM) comprise majority of human brain tumors. Despite advances in surgery, radiation, and chemotherapy, the prognosis for patients with malignant gliomas has not improved, emphasizing the need for a search for new chemotherapeutic drugs. The biological characteristics of these tumors are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of malignant gliomas. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. Deregulated p21-Ras function, as a result of mutation, overexpression, or growth factor-induced overactivation, contributes to the growth of GBM. The monoterpene perillyl alcohol (POH) has preventive and therapeutic effects in a wide variety of preclinical tumor models and is currently under phase I and phase II clinical trials. As inhibition of posttranslational isoprenylation of Ras, a family of proteins that are involved in signal transduction is among the drug-related activities observed in this compound; POH may be a potential chemotherapeutic agent for GBM. In vitro studies showed that POH was cytotoxic to Temozolomide (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. In this chapter, we summarize the current understanding of malignant gliomas signaling pathways with a focus on effect of intranasal delivery of POH in patients with relapsed malignant gliomas. Our results indicate that long-term POH inhalation chemotherapy is a safe and noninvasive strategy efficient for recurrent malignant glioma.