Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals

Abstract

Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage. Malignant tumors, such as glioblastoma multiforme, display elevated rates of oxygen consumption, necrosis and abnormal structural microvasculature. Alterations in the tumor microenvironment are tightly linked to tumor progression and occur as a result of activation of complex signaling networks involving inter-clonal cooperation, cell-matrix interactions and an ongoing inflammatory response leading to genetic and epigenetic alterations. This review will focus on the pro- and anti-oxidant activities of POH, which are greatly dependent on the respective ROS levels within the tumor microenvironment and involve the ER stress response system. As well, some critical aspects of tumor-associated metabolic changes and the consequences of endogenous ROS production for tumor progression will be discussed.

Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism

“…Besides, it seems plausible to hypothesize that due its pleiotropic nature, the monoterpene POH mitigates the overall impact of enzymatic MTHFR deficiency. This effect could be a result of POH-mediated indirect effects over additional metabolic and signaling pathways [53] that combined enhanced patients' survival regardless of individual gDNA methylation status. Hence, even though decreased MTHFR activity tend to increase DNA synthesis and support rapid tumor cell proliferation, POH inhaled treatment could partially overcome this enzymatic deficiency promoting cell cycle arrest, apoptosis and inhibiting ROS harmful effects [19].…”

“…Such encouraging findings result from the intranasal administration of POH, thus assuring the delivery of a pleiotropic compound with cytotoxic, pro-apoptotic, anti-inflammatory and antiangiogenic properties directly into the brain tissue. Moreover, delivery of POH through the intranasal route may avoid the hepatic first passage effect and maximize the direct antitumor effect of the treatment against malignant brain tumors [18][19][20].…”

Dynamic Luminescent Biosensors Based on Peptides for Oxygen Determination

“…Despite their toxic effects, moderate levels of ROS play a role in vital biological processes, such as biological signaling, chemical defense, biosynthetic reactions, etc. [12]. For instance, in biological signaling, the ROS act as secondary messengers in cellular adhesion, spreading, and migration, thus governing the proliferation and, ultimately, the survival of cells [13].…”

Circulating Cell-Free DNA as a Prognostic and Molecular Marker for Patients with Brain Tumors under Perillyl Alcohol-Based Therapy

“…Perillyl alcohol (POH) is a naturally occurring monoterpene, previously investigated via intranasal administration under a Phase II clinical trial, with very promising results for treatment of recurrent GBM temozolomide (TMZ)-resistant patients [ 20 , 21 ]. The therapeutic activity of POH is due to its cytotoxic, pro-apoptotic, anti-inflammatory and antiangiogenic properties [ 22 ], with no adverse effects reported so far for the intranasal (ITN) route of administration [ 20 ]. The blood–brain barrier (BBB) is compromised in patients with malignant brain lesions, but tumor progression may remain asymptomatic until patients are severely ill, partly because cerebrospinal fluid collected as an invasive procedure may not be routinely used for monitoring patients’ therapy response.…”