Sodium Butyrate Enhances Curcuminoids Permeability through the Blood-Brain Barrier, Restores Wnt/β-Catenin Pathway Antagonists Gene Expression and Reduces the Viability of Glioblastoma Cells

Abstract

Glioblastoma (GBM) is an extremely aggressive brain tumor awaiting novel, efficient, and minimally toxic treatment. Curcuminoids (CCM), polyphenols from Curcuma longa, and sodium butyrate (NaBu), a histone deacetylase inhibitor naturally occurring in the human body, await elucidation as potential anti-GBM agents. Thus, the aim of this study was to analyze CCM and NaBu both separately and as a combination treatment using three GBM cell lines. MTT was used for cytotoxicity evaluation, and the combination index was calculated for synergism prediction. Cell cycle, apoptosis, and reactive oxygen species (ROS) generation were analyzed using flow cytometry. DNA methylation was verified by MS-HRM and mRNA expression by qPCR. The permeability through the blood-brain barrier (BBB) and through the nasal cavity was evaluated using PAMPA model. The results of this study indicate that CCM and NaBu synergistically reduce the viability of GBM cells inducing apoptosis and cell cycle arrest. These effects are mediated via ROS generation and changes in gene expression, including upregulation of Wnt/β-catenin pathway antagonists, SFRP1, and RUNX3, and downregulation of UHRF1, the key epigenetic regulator. Moreover, NaBu ameliorated CCM permeability through the BBB and the nasal cavity. We conclude that CCM and NaBu are promising agents with anti-GBM properties.

Lichen-Derived Compounds and Extracts as Biologically Active Substances with Anticancer and Neuroprotective Properties

“…In brief, 1 × 10 4 cells per well were seeded on 96-well plates. After 24 h incubation, they were treated with varying concentrations of lichen-derived compounds (1, 5, 10, 25, 50 and 100 µM) and extracts (1,5,10,25,50 and 100 µg/mL). Cells treated with medium containing the respective concentrations of DMSO (Sigma-Aldrich, St. Louis, MO, USA) were used as a control.…”

“…Central nervous system (CNS) tumors are especially challenging, with glioblastoma multiforme (GBM) being one of the most deadly cancers. A growing body of evidence shows that natural bioactive molecules may serve well as an alternative approach to the treatment and control of GBM [1]. This prompted us to undertake further research on lichen-derived substances as important novel remedies useful in GBM therapy.…”

Natural Compounds in Liposomal Nanoformulations of Potential Clinical Application in Glioblastoma

“…This increased the compound’s activity in vitro and contributed to a favorable response in vivo compared to the free compound. In another study, A. Majchrzak-Celińska et al observed that the combination treatment of curcuminoids and sodium butyrate can also reveal a promising effect against GBM [ 74 ].…”

Ar-turmerone inhibits the proliferation and mobility of glioma by downregulating cathepsin B

“…Studies have confirmed that curcumin and a variety of curcumin compounds can inhibit cell growth and migration, induce DNA damage and promote early apoptosis in glioma cells; thus, these compounds have been identified as potential anti-glioma drugs [ 26 , 27 ]. Majchrzak et al demonstrated that sodium butyrate increased the permeability of curcumin through the blood-brain barrier, thus restoring the expression of Wnt/β-catenin pathway antagonist genes and reducing the vitality of glioblastoma cells [ 28 ]. Liu et al found that β-elemene enhanced the radiosensitivity and chemical sensitivity of glioblastoma cells by inhibiting the ataxia telangiectasia mutated signaling pathway [ 26 ].…”