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Page 8 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58

Table 2. Histone deacetylase enzyme inhibitor classes
HDAC inhibitor class HDAC inhibitor(s)* HDAC target Clinical trial in GBM Clinical trial for other uses
Hydroxamic acid ABHA AR-42 in Phase I (acute myeloid leukemia)
m-Carboxycinnamic CBHA Panobinostat in Phase III (several cancers)
LAQ824 Quinostat in Phase II (T-cell lymphoma)
AR-42 Vorinostat in Phase III (cutaneous T-cell
Panobinostat HDAC classes I, II, Panobinostat in Phase II lymphoma and other cancers)
Belinostat in Phase II
Quisinostat and IV Belinostat indicated for use in treatment of
SBHA SAHA in Phase III peripheral T-cell lymphoma
TSA
Vorinostat
Belinostat
Short-chain fatty acid Pivanex Pivanex in Phase II (non-small cell lung
Sodium butyrate cancer)
Buphenyl Sodium butyrate in Phase II (endogenous
Valproate antibiotics in gut)
HDAC classes I and Buphenyl in Phase II Buphenyl indicated for use in treatment of
II Valproate in Phase II
urea cycle disorders
Valproate indicated for use in treatment of
epilepsy, anorexia nervosa, panic attack,
and anxiety disorders.
Benzamide Entinostat HDAC1, HDAC2, Not available Entinostat in Phase III (breast cancer)
and HDAC3
Cyclic peptide Romidepsin Romidepsin indicated for use in treatment
HDAC1, HDAC2, Phase I/II of cutaneous T-cell lymphoma and in
HDAC3, and HDAC8
Phase trials for many other cancers
Other DATS Unknown for DATS
Tubacin HDAC6 for Tubacin Not available Not available
*HDAC inhibitors have been divided into four classes based on chemical makeup and HDAC classes they inhibit. Hydroxamic acid
derivatives are some of the most well-described HDAC inhibitors and inhibit the classical HDAC family of enzymes. Pabinostat,
bellinostat, and SAHA are all at the clinical trial phase of development for use in GBM, with numerous other compounds showing
efficacy in clinical trials for other tumors. Short-chain fatty acid HDAC inhibitors are also relatively well described and inhibit class I
and II HDAC enzymes. Buphenyl and valproate are both in the clinical trials for use in GBM with numerous other compounds showing
efficacy in clinical trials for other tumors. Entinostat is the sole benzamide derivative HDAC inhibitor and it has been shown to inhibit
class I HDAC enzymes. This compound has not yet been used in clinical trials for treatment of GBM but has gone to a phase III clinical
trial for treatment of breast cancer. Romidepsin is the sole cyclic peptide derivative HDAC inhibitor and it has also been shown to inhibit
class I HDAC enzymes. This compound has gone to phase I and II clinical trials for use in GBM and it has been approved for treatment of
cutaneous T-cell lymphoma. Finally, DATS and tubacin are miscellaneous HDAC inhibitors that are currently under investigation and they
have variable effects on specific HDAC enzymes. HDAC: histone deacetylase; ABHA: azlaic bishydroxamic acid; CBHA: carboxycinnamic
bishydroxamic acid; SBHA: suberic bishydroxamic acid; TSA; trichostatin A; DATS: diallyl trisulfide; GBM: glioblastoma multiforme

[55]
or in combination regimens . Ultimately, there is a more vested interest in the clinical outcomes and
efficacy, but in order for these clinical trials to be well reasoned there must be a strong research base and
rationale behind the use of HDAC inhibitors.

There is a two-fold rationale for the use of HDAC inhibitors in glioblastoma therapy. First, HDAC inhibitors
promote a more open chromatin conformation in the tumor cells and thereby permit the DNA alkylating
chemotherapeutic agents (e.g., TMZ) to access genomic DNA and increase the sensitivity of the tumor
cells for these agents. Second, HDAC inhibitors help reverse some of the abnormal genetic silencing in
glioblastoma, where it is presumed that this will lead to enhanced cell-cycle arrest and apoptosis from the
[58]
action of DNA damaging agents . SAHA plays a unique role as an HDAC inhibitor that acts as a pan-
inhibitor of all HDAC enzymes, while other HDAC inhibitors are more specific in their action. All the
HDAC inhibitors, however, seem to cause increases in acetylation in histone and non-histone proteins and
reactivate p21Waf1/Cip1, a protein that contributes to cell-cycle arrest due to its role as a tumor suppressor
[59]
protein . Traditionally, it has been believed that all HDAC inhibitors have difficulty in penetrating the BBB
at low doses and require high doses for therapeutic effects. Some selective HDAC inhibitor classes such as
[61]
[60]
the fatty acids and benzamide compounds , however, have shown increased penetration into the BBB on
imaging studies. Interestingly enough, it also seems that there is some selectivity between HDAC inhibitors
affecting tumor cells vs. normal cells. One older study, in particular, found that the antitumor effects of