Histone inhibitor as a putative radiosensitizer in pediatric glioblastoma cell line

Abstract

Glioblastoma (GBM) is one of the most aggressive tumors affecting the central nervous system (CNS). It is classified in primary GBM, diagnosed primarily, and in secondary GBM, when tumor evolves from low-grade or anaplastic glial lesions. The standard treatment for GBM consists primarily of surgical resection, radiotherapy and chemotherapy (temozolomide (TMZ) and other alkylating agents). Yet, the prognosis remains very poor, and children with GBM have a median overall survival of 12 to 15 months. Moreover, chemotherapy and radiotherapy are potentially toxic and may contribute to the increase in mortality and morbidity rates of long-term survivors. Epigenetic mechanisms may interfere with the process of carcinogenesis, and the acetylation of DNA can modulate the expression of genes that act in cell cycle control and contribute to the development and progression of malignancies. Clinical studies have shown that histone deacetylases (HDACs) inhibitors, in combination with other therapeutic agents, are clinically active and well tolerated in the treatment of a wide variety of tumors. These inhibitors can sensitize the cellular response to ionizing radiation and cause a reduction in the standard doses of radiation offered to patients, minimizing side effects. Ionizing radiation induces DNA damage and is generally accepted that the double-stranded breaks (DSBs) is the most severe type of injury related to cell survival and preservation of genomic integrity. The present study aims to assess the potential effect of the radiosensitizer abexinostato (PCI-24781), a new and potent pan-HDAC inhibitor in pediatric glioblastoma cell line (SF188). The effect of irradiation on proliferation rates, clonogenicity and apoptosis will be compared between SF188 cell-line pretreated or not with PCI-24781. It will be also analyzed the effects of abexinostato on the expression of some key proteins responsible for the double-stranded breaks repair caused by irradiation, correlating the observed effects on cellular dynamics and with the genetic and epigenetic pathways potentially involved in the therapy with PCI-24781. (AU)