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.

Robert Kleszcz,Judyta Cielecka-Piontek,Anna Stasiłowicz-Krzemień,Aleksandra Majchrzak-Celińska

doi:10.3390/ijms222011285

Robert Kleszcz, Judyta Cielecka-Piontek + Show 2 more

Open Access

https://doi.org/10.3390/ijms222011285

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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.

Highlights

More than 24,500 new cases of the brain & other nervous system tumors and more than 18,500 deaths are estimated to occur in 2021 in the United States [1]
We found that the RASSF1A methylation level was diminished when Aza was used, while U-138 MG cells were resistant to its hypomethylating properties
The results of our study indicate that curcumin, with the Papp value of 5.337 × 10−6 ± 2.424 × 10−7 cm s−1 can be considered highly permeable through the nasal cavity membranes (Figure 13)

Summary

Introduction

More than 24,500 new cases of the brain & other nervous system tumors and more than 18,500 deaths are estimated to occur in 2021 in the United States [1]. Brain and other nervous system tumors are the leading cause of cancer death among men aged

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