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Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas.
Surg Neurol Int 2016; 7:1SN

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.

Authors+Show Affiliations

Department of General and Specialized Surgery, Antonio Pedro University Hospital, Fluminense Federal University, Rio de Janeiro, Brazil.Memphys-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, California, USA.Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, California, USA.Retired Professor from the Rio de Janeiro Federal University, Rio de Janeiro, Brazil.Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Rio de Janeiro, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26862440

Citation

da Fonseca, Clovis Orlando, et al. "Perillyl Alcohol: Dynamic Interactions With the Lipid Bilayer and Implications for Long-term Inhalational Chemotherapy for Gliomas." Surgical Neurology International, vol. 7, 2016, p. 1.
da Fonseca CO, Khandelia H, Salazar MD, et al. Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas. Surg Neurol Int. 2016;7:1.
da Fonseca, C. O., Khandelia, H., Salazar, M. D., Schönthal, A. H., Meireles, O. C., & Quirico-Santos, T. (2016). Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas. Surgical Neurology International, 7, p. 1. doi:10.4103/2152-7806.173301.
da Fonseca CO, et al. Perillyl Alcohol: Dynamic Interactions With the Lipid Bilayer and Implications for Long-term Inhalational Chemotherapy for Gliomas. Surg Neurol Int. 2016;7:1. PubMed PMID: 26862440.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas. AU - da Fonseca,Clovis Orlando, AU - Khandelia,Himanshu, AU - Salazar,Marcela D'Alincourt, AU - Schönthal,Axel H, AU - Meireles,Osório C, AU - Quirico-Santos,Thereza, Y1 - 2016/01/05/ PY - 2015/03/25/received PY - 2015/10/26/accepted PY - 2016/2/11/entrez PY - 2016/2/11/pubmed PY - 2016/2/11/medline KW - Chemotherapy for gliomas KW - intranasal administration KW - long-term survival KW - membrane potentials KW - molecular dynamics simulation KW - perillyl alcohol SP - 1 EP - 1 JF - Surgical neurology international JO - Surg Neurol Int VL - 7 N2 - 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. SN - 2229-5097 UR - https://www.unboundmedicine.com/medline/citation/26862440/Perillyl_alcohol:_Dynamic_interactions_with_the_lipid_bilayer_and_implications_for_long_term_inhalational_chemotherapy_for_gliomas_ L2 - http://www.surgicalneurologyint.com/article.asp?issn=2152-7806;year=2016;volume=7;issue=1;spage=1;epage=1;aulast=da DB - PRIME DP - Unbound Medicine ER -