Abstract
BACKGROUND
Histone deacetylase inhibitors (HDACi) are increasingly investigated as potential therapeutics in various cancers, including the most common brain malignancy, glioblastoma multiforme (GBM). The compound MI-192 has demonstrated selective inhibition of subtypes HDAC2 and 3, reportedly involved in tubulin acetylation and mitosis which drive migration and proliferation.
METHODS
The anti-migratory and anti-proliferative activity of MI-192 was investigated at two different concentrations (1,10 µM) in 3D invasion assays with spheroids developed from tumour core and edge cell populations of the patient-derived glioblastoma cell line GBM40. In addition, data was also generated using 2D scratch wound assays and immunofluorescence staining for Ki67 (proliferation), Nestin and SOX2 (stemness), Cleaved caspase 3 (apoptosis), HDAC 2 and 3 expression.
RESULTS
GBM40 core and edge cell tumour populations displayed distinct phenotypes and differential cell marker expression levels. In 2D assays core-derived cells proliferated in close proximity to one another whereas edge cells displayed an invasive phenotype with individual lamellopodia and focal adhesions. SOX2 and nestin expression were altered in both core and edge-cell populations in response to HDAC inhibition, with both markers displaying upregulated expression in edge-derived cells. Core cells displayed significantly decreased SOX2 expression levels at 10µM MI-192. 3D spheroids increased in core area size and demonstrated decreased migration at 1µM concentrations, with the reverse occurring at 10µM.
DISCUSSION
This study supports the idea that there are two distinct stem cell populations mediated via SOX2 and nestin, which predominate at specific sites within the tumour cell subpopulations. MI-192 may be a potential therapeutic for the clinical management of GBM affecting tubulin acetylation, SOX2 and nestin expression. This activity appears concentration dependent, inducing a proliferative and less invasive state at low concentration, potentially promoting greater tumour susceptibility to radiotherapy. Further studies are required to determine the in vivo effects of this compound in combination with radiation.
Histone deacetylase inhibitors (HDACi) are increasingly investigated as potential therapeutics in various cancers, including the most common brain malignancy, glioblastoma multiforme (GBM). The compound MI-192 has demonstrated selective inhibition of subtypes HDAC2 and 3, reportedly involved in tubulin acetylation and mitosis which drive migration and proliferation.
METHODS
The anti-migratory and anti-proliferative activity of MI-192 was investigated at two different concentrations (1,10 µM) in 3D invasion assays with spheroids developed from tumour core and edge cell populations of the patient-derived glioblastoma cell line GBM40. In addition, data was also generated using 2D scratch wound assays and immunofluorescence staining for Ki67 (proliferation), Nestin and SOX2 (stemness), Cleaved caspase 3 (apoptosis), HDAC 2 and 3 expression.
RESULTS
GBM40 core and edge cell tumour populations displayed distinct phenotypes and differential cell marker expression levels. In 2D assays core-derived cells proliferated in close proximity to one another whereas edge cells displayed an invasive phenotype with individual lamellopodia and focal adhesions. SOX2 and nestin expression were altered in both core and edge-cell populations in response to HDAC inhibition, with both markers displaying upregulated expression in edge-derived cells. Core cells displayed significantly decreased SOX2 expression levels at 10µM MI-192. 3D spheroids increased in core area size and demonstrated decreased migration at 1µM concentrations, with the reverse occurring at 10µM.
DISCUSSION
This study supports the idea that there are two distinct stem cell populations mediated via SOX2 and nestin, which predominate at specific sites within the tumour cell subpopulations. MI-192 may be a potential therapeutic for the clinical management of GBM affecting tubulin acetylation, SOX2 and nestin expression. This activity appears concentration dependent, inducing a proliferative and less invasive state at low concentration, potentially promoting greater tumour susceptibility to radiotherapy. Further studies are required to determine the in vivo effects of this compound in combination with radiation.
| Original language | English |
|---|---|
| Pages (from-to) | 231 |
| Number of pages | 1 |
| Journal | Neuro-Oncology |
| Volume | 19 |
| DOIs | |
| Publication status | Published - Nov 2017 |
| Externally published | Yes |
| Event | 22nd Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology - San Francisco, United States Duration: 16 Nov 2017 → 19 Nov 2017 Conference number: 22 |
