Page 377 - Read Online

Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58 Page 7 of 18

progression through direct inhibition of HDAC enzymes, thereby providing genetic evidence of a direct
cellular target that TSA acted to inhibit fungal growth. A few years later, a fungal cyclic peptide known
as trapoxin was also found to strongly inhibit HDACs, this time displaying an irreversible enzymatic
[51]
inhibition . These compounds served as a proof of premise, where HDACs could be inhibited with the use
of exogenous compounds. However, these compounds had yet to find a clinical use.

In 1998, two later compounds to be clinically significant HDAC inhibitors were reported in the literature:
suberanilohydroxamic acid (SAHA) also known as vorinostat and FK228 also known as romidepsin [52,53] .
Phase I clinical trials of FK228 conducted at the National Cancer Institute confirmed that this compound
was effective for the therapy of cutaneous and peripheral T-cell lymphoma. This finding stimulated the
interest of many researchers and began increased development of HDAC inhibitors towards the treatment
of multiple cancers. After years of drug development, SAHA (vorinostat) was the first HDAC inhibitor
[54]
approved for use in cancer chemotherapy with FK228 following closely behind a few years later for
approval in 2009. Multiple derivatives and novel compounds followed these two prototypic HDAC inhibitors,
ultimately going on to have many investigational compounds being researched, all towards modifying the
epigenetic expression in tumor cells through the inhibition of HDAC enzymes.

The HDAC inhibitors available today have wide variations in their function, structure, and mechanism.
These inhibitors (similarly to their HDAC enzyme targets) can be divided into four classes on the basis of
their chemical structure: hydroxamate, short-chain fatty acid (carboxylate), benzamide, and cyclic peptides
[Table 2]. Adapted from recent investigations [55,56] and clinical trial records from the National Institutes
of Health, these agents and their various progress towards approval by the United States Food and Drug
Administration (FDA) for use in glioblastoma has been compiled. The hydroxamic acid derivatives now
include the compounds of azlaic bishydroxamic acid, m-carboxycinnamic bishydroxamic acid, dacinostat
(LAQ824), a novel HDAC inhibitor known only as AR-42, panobinostat (LBH-589), quisinostat, and
suberic bishydroxamic acid, among the already known compounds TSA and SAHA. Short-chain fatty
acid derivatives include pivaloyloxymethyl butyrate (pivanex, AN-9), sodium butyrate, buphenyl (sodium
phenylbutyrate), and valproic acid. Benzamides include the lone HDAC inhibitor entinostat (MS-275) and
cyclic peptides still include the lone inhibitor of romidepsin. Miscellaneous agents displaying HDAC
inhibitory activity include diallyl trisulfide (DATS) and tubacin. The above agents have shown clinical
efficacy against many clinical entities but are most notable in their ability to be used in cancer chemotherapy.

The precise mechanism for which HDAC inhibitors ultimately cause an anti-cancer effect is not completely
understood. These agents typically inhibit cancer cell proliferation through causation of cell cycle arrest,
differentiation, and/or apoptosis. Studies show that all HDAC inhibitors activate either the extrinsic
or intrinsic pathways of apoptosis in cancer models (when used in a combination therapy), with some
[57]
activating both apoptotic pathways . As we will discuss later, these agents have also been found to play
an immunomodulatory role against tumor cells as well. Ultimately, the mechanism for which these HDAC
inhibitors exert their cellular changes does not need to be completely understood to observe clinical changes
and the promise of these novel therapies. Some of these agents have already been approved for use and are in
multiple phases of clinical trials towards the treatment of many pathologies [Table 2]. However, none of these
agents have yet been approved for clinical use in the treatment of glioblastoma, a tumor that is in desperate
need of novel therapeutics due to its dismal 5-year survival rates.

HDAC INHIBITORS FOR ANTITUMOR EFFECTS IN GLIOBLASTOMA
Glioblastoma, as one of the deadliest human neoplasms with few effective treatment options, has frequently
been a target of new treatment modality through clinical trials. HDAC inhibitors are no exception to this
and these inhibitors have undergone multiple clinical trials to test their efficacy in glioblastoma. These agents
have displayed both pre-clinical efficacy in their use, as well as efficacy in clinical use either as monotherapy