Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas

Abstract

Background:Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may contribute to the development of drug resistance. Biophysical interactions between therapeutic agents and the lipid components at the outer plasma membrane interface are critical for effective drug uptake. Amphipathic molecules such as perillyl alcohol (POH) have a high partition coefficient and generally lead to altered lipid acyl tail dynamics near the lipid-water interface, impacting the lipid bilayer structure and transport dynamics. We therefore hypothesized that glioma cells may display enhanced sensitivity to POH-induced apoptosis due to plasma membrane alterations, while in non-transformed cells, POH may be expelled through thermal agitation.Methods:Interactions between POH and the plasma membrane was studied using molecular dynamics simulations. In this phase I/II trial, we set up to evaluate the clinical effectiveness of long-term (up to 5 years) daily intranasal administration of POH in a cohort of 19 patients with low-grade glioma (LGG). Importantly, in a series of clinical studies previously published by our group, we have successfully established that intranasal delivery of POH to patients with malignant gliomas is a viable and effective therapeutic strategy.Results:POH altered the plasma membrane potential of the lipid bilayer of gliomas and prolonged intranasal administration of POH in a cohort of patients with LGG halted disease progression with virtually no toxicity.Conclusion:Altogether, the results suggest that POH-induced alterations of the plasma membrane might be contributing to its therapeutic efficacy in preventing LGG progression.

Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats

“…Inhalation of POH resulted in readily detectable amounts of this agent in the systemic circulation, which is intriguing because clinical studies of oral POH in cancer patients 13,14 as well as studies in rats, 35,36 while detecting PA, were unable to detect the parent drug POH in serum. Inhalation of POH resulted in readily detectable amounts of this agent in the systemic circulation, which is intriguing because clinical studies of oral POH in cancer patients 13,14 as well as studies in rats, 35,36 while detecting PA, were unable to detect the parent drug POH in serum.…”

“…The chromatographic method developed in this research was shown to be practical and sufficiently sensitive to determine and quantify the presence of POH and its metabolite PA in different biological matrices. Inhalation of POH resulted in readily detectable amounts of this agent in the systemic circulation, which is intriguing because clinical studies of oral POH in cancer patients 13,14 as well as studies in rats, 35,36 while detecting PA, were unable to detect the parent drug POH in serum. Rather, an optimized, elaborate gas chromatographic-mass spectrometric (GC-MS) method was required to detect intact POH in plasma from a patient and rat .37 This aspect points to the intriguing possibility that inhalation of POH perhaps might result in overall higher systemic levels of POH than are possible to achieve with oral administration.…”

“…In addition, many other tumor types were found to be responsive to POH treatment in vitro and in vivo, which formed the basis for subsequent clinical studies. 13 In the United States, similar phase I/II studies with intranasal NEO100, a highly purified version of POH, were started in 2016 (NCT02704858). In fact, the unremitting nature of these side effects resulted in several subjects declining further participation in these trials.…”

“…There were no long-term central nervous system or systemic severe adverse events, even over years of daily administration, and patient compliance remained very high. 13 In the United States, similar phase I/II studies with intranasal NEO100, a highly purified version of POH, were started in 2016 (NCT02704858).…”

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

“…Perillyl alcohol (POH) is a natural compound belonging to the group of hydroxylated monoterpenes found in many kinds of essential oils (peppermint, spearmint, cherries and others) [100]. The amphipathic character of POH makes it readily soluble in biological membranes and capable to modulate the lipid bilayer of gliomas cells, leading to an effective POH delivery into these cells [101]. A post translational Ras inhibition effect has been suggested by some studies as the main mechanism of anticancer action of POH, however it is not observed in others, thus the action of POH is often described as pleiotropic, affecting different cell growth regulation processes [102].…”