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Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58 Page 9 of 18

[62]
hydroxamate-containing HDAC inhibitors displayed antitumor selectivity and did not affect somatic cells ,
apprising the possibility of a safe agent with few toxicities to normal cells. Additionally, HDAC transcripts
have been observed to be both increased and decreased in tumor cells undergoing exposure to HDAC
[63]
inhibiting agents . The results showed a lack of clear-cut cell cycle arrest effect, which the researchers
recognized during other pre-clinical studies. The lack of specificity on HDAC substrates by HDAC inhibitors
presents a mechanistic grey area concerning the use of HDAC inhibitors in glioblastoma specifically.

HDAC inhibitors have also shown efficacy in the preclinical arena towards the chemotherapy of GSCs.
Targeting GSCs in particular is a major therapeutic undertaking as these cells often form the seeds of
recurrence for glioblastoma after initial therapy and also confer resistance to previously used standard-of-
care therapeutic agents. One study showed that the HDAC inhibitors TSA and valproic acid significantly
reduced proliferation rates of GSCs by decreasing the amount of neural and embryonic stem cell surface
markers expressed by these cells, indicating that these HDAC inhibitors stimulated differentiation in
GSCs . The HDAC inhibitor SAHA also demonstrated capabilities of slowing down tumor proliferation
[64]
and triggering autophagy in GSCs, rather than induction of differentiation seen with TSA and valproic
acid . HDAC inhibitors have also been implicated for use in combination therapies against GSCs.
[65]
Another study demonstrated that combination of the HDAC inhibitors SAHA, valproic acid, and sodium
phenylbutyrate when used in combination with the FDA-approved proteasome inhibitor bortezomib caused
[66]
high cytotoxicity against GSCs in cultures . Specific chemotherapy that targets GSCs is in high demand
as effective treatments for recurrent glioblastoma shows very poor efficacy. At least in the preclinical
arena, HDAC inhibitors have demonstrated their efficacy in targeting GSCs in particular either through
monotherapy or in combination with other known therapies.

Regarding current clinical trials under way for each specific HDAC inhibitor towards the treatment of
glioblastoma, many HDAC inhibitors have shown considerable clinical promise but have yet to be approved
by the FDA. These agents are said to be in the pre-clinical phase, where there are multiple rationales for
specific inhibitors. Beginning with the examination of the hydroxamate derivative compounds, SAHA
(vorinostat) has been shown in vitro to inhibit cell proliferation in glioblastoma cell lines independent of
their p53 status, leading to an accumulation of cells arrested in the G2/M phase of the cell cycle, increased
[67]
expression of anti-proliferative genes, and decreased levels of pro-growth genes . SAHA additionally
induces differentiation, apoptosis, and autophagy in human glioblastoma cell lines. As mentioned earlier,
TSA is another hydroxamate compound akin to SAHA in HDAC targets. Similar to SAHA, TSA also induces
differentiation and apoptosis in human glioblastoma cell lines, resulting in a higher expression of astrocyte-
specific markers [i.e., glial fibrillary acidic protein (GFAP)] and reduced expression of vimentin and nestin
[68]
(common markers of neuro-epithelial stem cells) , increasing the recognizability of the tumor cells to the
immune system. Of the short-chain fatty acid HDAC inhibitor class, valproic acid has been found to exhibit
its antineoplastic effects through decreasing the activity and expression levels of matrix metalloproteinases
(MMPs) in addition to the inhibition of activity of HDAC class I and II, thereby decreasing the invasiveness
[69]
of glioblastoma cell lines . Phenylbutyrate, another short-chain fatty acid HDAC inhibitor, has
demonstrated its efficacy (like TSA) through increasing the expression of GFAP in human glioblastoma
cells in culture as well as redistributing intracellular GFAP thereby enhancing gap junction communication
between tumor cells through upregulation of the protein connexin 43 [68,70] . Entinostat, the lone benzamide
HDAC inhibitor, has been shown as a promising compound in the treatment of glioblastoma through its
ability to significantly reduce cell growth, upregulate the cell cycle inhibitor p21Waf1/Cip1 and induce cell
[71]
cycle arrest in the G0/G1 phase, and induce apoptotic cell death in glioblastoma cell lines . Entinostat has
also been shown to have some immunomodulatory roles similar to TSA through regulation of production
[72]
of cytokines and inhibiting Treg cells in certain cancer models . Romidepsin, the lone cyclic peptide
HDAC inhibitor, has been shown at nanomolar levels in glioblastoma cell lines to cause inhibition of
cell proliferation and induction of apoptosis (through the increased expression of the cell cycle inhibitor