Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study

Author(s)

Silva, Marcela de Oliveira ^[1] ; de Sousa, Graziella Ribeiro ^[1] ; Simoes, Sarah Capelupe ^[1] ; Nicolucci, Patricia ^[2] ; Tamashiro, Edwin ^[1] ; Saggioro, Fabiano ^[1] ; de Oliveira, Ricardo Santos ^[1] ; Brassesco, Maria Sol ^[3]

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Sch Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Phys, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Lab Cell Biol & Oncogenet, Dept Biol, Fac Philosophy Sci & Letters Ribeirao Preto, Ave Bandeirantes, 3900, BR-14040900 Sao Paulo - Brazil

• Document type: Journal article
• Source: CHILD'S NERVOUS SYSTEM; v. 37, n. 7, p. 2163-2175, JUL 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 16/08125-5 - Investigation of anti-proliferative and anti-invasive effects of perillyl alcohol on medulloblastoma-SHH and its influence on the modulation Ras and its effectors
• Grantee: Marcela de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/23881-2 - Evaluation of the antiproliferative effects of Perillyl Alcohol in Medulloblastoma cell lines
• Grantee: Marcela de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Scientific Initiation