Marcela de Oliveira Silva1, Graziella Ribeiro de Sousa1, Sarah Capelupe Simões1, Patrícia Nicolucci2, Edwin Tamashiro1, Fabiano Saggioro1, Ricardo Santos de Oliveira1, María Sol Brassesco3. 1. Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil. 2. Physics Department from the Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil. 3. Laboratory of Cell Biology and Oncogenetics, Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, São Paulo, CEP 14040-900, Brazil. solbrassesco@usp.br.
Abstract
PURPOSE: Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting. METHODS: The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated with intraperitoneal injections. Alternatively, animals with intracranial tumors were exposed to intranasal POH alone or combined with radiation. Tumor growth was measured by bioluminescence. Analyses of cytotoxicity to the nasal cavity were also performed, and the presence of POH in the brain, lungs, and plasma was surveyed through chromatography/mass spectrometry. RESULTS: POH decreased cell proliferation and colony formation, with conspicuous death, though the invasive capacity was only affected in the NRAS-mutated cell line. Median-drug effect analysis displayed synergistic combinations with methotrexate. Otherwise, POH showed to be a reasonable radiosensitizer. In vivo, intraperitoneal injection significantly decreased tumor volume. However, its inhalation did not affect orthotopic tumors, neither alone or followed by cranial irradiation. Nasal cavity epithelium showed unimportant alterations, though, no traces of POH or its metabolites were detected in tissue samples. CONCLUSION: POH presents robust in vitro antimedulloblastoma effects and sensitizes cell lines to other conventional therapeutics, reducing tumor volume when administered intraperitoneally. Nevertheless, further improvement of delivery devices and/or drug formulations are needed to better characterize its effectiveness through inhalation.
PURPOSE: Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting. METHODS: The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated with intraperitoneal injections. Alternatively, animals with intracranial tumors were exposed to intranasal POH alone or combined with radiation. Tumor growth was measured by bioluminescence. Analyses of cytotoxicity to the nasal cavity were also performed, and the presence of POH in the brain, lungs, and plasma was surveyed through chromatography/mass spectrometry. RESULTS: POH decreased cell proliferation and colony formation, with conspicuous death, though the invasive capacity was only affected in the NRAS-mutated cell line. Median-drug effect analysis displayed synergistic combinations with methotrexate. Otherwise, POH showed to be a reasonable radiosensitizer. In vivo, intraperitoneal injection significantly decreased tumor volume. However, its inhalation did not affect orthotopic tumors, neither alone or followed by cranial irradiation. Nasal cavity epithelium showed unimportant alterations, though, no traces of POH or its metabolites were detected in tissue samples. CONCLUSION: POH presents robust in vitro antimedulloblastoma effects and sensitizes cell lines to other conventional therapeutics, reducing tumor volume when administered intraperitoneally. Nevertheless, further improvement of delivery devices and/or drug formulations are needed to better characterize its effectiveness through inhalation.