title: 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.
  
  
  CONCLUSIONS
  Altogether, the results suggest that POH-induced alterations of the plasma membrane might be contributing to its therapeutic efficacy in preventing LGG progression.
authors: Department of General and Specialized Surgery, Antonio Pedro University Hospital, Fluminense Federal University, Rio de Janeiro, Brazil.
authors: Clovis Orlando
authors: CO
authors: da Fonseca
authors: Memphys-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.
authors: Himanshu
authors: H
authors: Khandelia
authors: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, California, USA.
authors: Marcela D'Alincourt
authors: MD
authors: Salazar
authors: Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, California, USA.
authors: Axel H
authors: AH
authors: Schönthal
authors: Retired Professor from the Rio de Janeiro Federal University, Rio de Janeiro, Brazil.
authors: Osório C
authors: OC
authors: Meireles
authors: Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Rio de Janeiro, Brazil.
authors: Thereza
authors: T
authors: Quirico-Santos
keywords: Chemotherapy for gliomas; intranasal administration; long-term survival; membrane potentials; molecular dynamics simulation; perillyl alcohol