Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents

Figures & data

Table 1 Classification of the eleven metal-dependent histone deacetylase (HDAC) enzymes

HDAC enzyme	Size (amino acid)	Chromosomal size	Localization
Class I (Rpd3)
HDAC1	482	1p34.1	Nucleus
HDAC2	488	6q21	Nucleus
HDAC3	428	5q31.3	Nucleus
HDAC8	377	Xq13	Nucleus/cytoplasm
Class IIa (Hda1)
HDAC4	1084	2q37.2	Nucleus/cytoplasm
HDAC5	1122	17q21	Nucleus/cytoplasm
HDAC7	912	12q13.1	Nucleus/cytoplasm
HDAC9	1069	7p12.1	Nucleus/cytoplasm
Class IIb (Hda1)
HDAC6	1215	Xp11.22	Cytoplasm
HDAC10	669	22q13.3	Cytoplasm
Class IV (Rpd3/Hda1)
HDAC11	347	3p25.2	Nucleus/cytoplasm

Table 2 Partial list of nonhistone protein substrates of HDACs

Effect of acetylation	Protein	Intracellular function	HDAC implicated	References
Increased DNA-binding affinity	p53	Tumor suppressor		129
	SRY	Transcription factor	HDAC3	130
	STAT3	Signaling mediator	HDAC1, −2, −3	131
	GATA1	Transcription factor	HDAC3, −4, −5	132
	GATA2	Transcription factor	HDAC3, −5	133
	E2F1	Transcription factor	HDAC1	134
	MyoD	Transcription factor	HDAC1	135
Decreased DNA-binding affinity	YY1	Transcription factor	HDAC1, −2, −3	136
	HMG-A1	Nuclear factor		137
	HMG-N2	Nuclear factor		138
	p65	Transcription factor		139
Increased transcriptional activation	p53	Tumor suppressor		129, 140
	HMG-A1	Nuclear factor		141
	STAT3	Signaling mediator	HDAC1, −2, −3	131, 142
	AR	Nuclear receptor	HDAC1	143, 144
	ERα (basal)	Steroid hormone receptors	HDAC1	145
	GATA1	Transcription factor	HDAC3, −4, −5	132
	GATA2	Transcription factor	HDAC3, −5	133
	GATA3	Transcription factor		146
	EKLF	Transcription factor	HDAC1	147
	MyoD	Transcription factor	HDAC1	135
	E2F1	Transcription factor	HDAC1	134, 148
	RUNX3	Tumor suppressor	HDAC1, −5	149
Decreased transcriptional activation	ERα (ligand-dependent)	Steroid hormone receptors	HDAC1	145
	HIF1α	Transcription factor		150
Increased protein stability	p53	Tumor suppressor	HDAC1	151
	c-MYC	Oncoprotein		152
	AR	Nuclear receptor	HDAC1	153
	ERα	Steroid hormone receptors	HDAC1	154
	E2F1	Transcription factor	HDAC1	134
	Smad7	Signaling mediator	HDAC1, −3	155
	RUNX3	Tumor suppressor	HDAC1, −5	149
Decreased protein stability	HIF1α	Transcription factor		150
Promotes protein–protein interaction	STAT3	Signaling mediator	HDAC1, −2, −3	131
	AR	Nuclear receptor	HDAC1	156
	EKLF	Transcription factor	HDAC1	157
	Importin α	Nuclear import factors		158
Disrupts protein–protein interaction	NF-κB	Transcription factor		159
	Ku70	DNA-repair protein		160
	Hsp90	Chaperone	HDAC6	161

Abbreviations: SRY, sex-determining region Y; STAT, signal transducer and activator of transcription; GATA, GATA-binding factor; E2F, E2F transcription factor; MyoD, myogenic differentiation; YY1, transcriptional repressor protein; HMG, High Mobility Group; AR, androgen receptor; ER, estrogen receptor; EKLF, Erythroid Kruppel-like factor; RUNX, Runt-related transcription factor; HIF, Hypoxia-inducible factor; NF-kB, nuclear factor kappa-B; Ku70, ATP-dependent DNA helicase; Hsp, heat-shock protein.

Table 3 Characteristics of histone deacetylase (HDAC) inhibitors currently undergoing clinical trials

HDAC inhibitor	Structure	HDAC class specificity	Potency	Clinical trials
Hydroxamic acids
Trichostatin A (TSA)		I, II, IV	nM	–
Vorinostat (suberoylanilide hydroxamic acid, SAHA)		I, II, IV	nM	FDA-approved (2006), phase II, III
Givinostat (ITF2357)		I, II	nM	Phase I, II
Abexinostat (PCI-24781)		I, II, IV	nM	Phase I, II
Belinostat (PXD101)		I, II, IV	μM	Phase I, II
Panobinostat (LBH589)		I, II, IV	μM	Phase II, III
Resminostat (4SC-201)		I, II, IV	μM	Phase I, II
Quisinostat (JNJ-26481585)		I, II, IV	μM	Phase I
Cyclic peptide
Depsipeptide (romidepsin)		I	nM	FDA-approved (2009), phase I, II
Benzamides
Entinostat (MS-275)		I	μM	Phase II
Mocetinostat (MGCD0103)		HDAC1	μM	Phase I, II
Fatty acids
Valproic acid (VPA)		I, II	mM	Phase I, II, III
Butyrate		I, II	mM	Phase II

Figure 1 HDAC inhibitors promote the acetylation of histones and nonhistone proteins by inhibiting the activity of HDAC enzymes.

Notes: HDAC inhibitor-mediated modification of histones and nonhistone proteins (examples shown) can result in increased or decreased gene expression, influencing other DNA-based processes, including DNA replication and repair. As a result of these processes, HDAC inhibitors are able to elicit a multitude of biological effects on cells, such as apoptosis, cell-cycle arrest, and angiogenesis.
Abbreviations: HDACIs, histone deacetylase inhibitors; HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor.

Table 4 Partial list of current clinical trials involving histone deacetylase inhibitors as single and combination therapies

Treatment	Phase	Disease	Patient number	Dose	Safety/efficacy
Single agents
Vorinostat	IIa	Myelodysplastic syndromes, bone marrow disease	A: 10 patients	A: 400 mg daily; 21-day cycles up to 8 cycles	Total SAEs, 3/22; lack of efficacy, 10/22; progressive disease, 1/22; response rate, 0/21
			B: 12 patients	B: 200 mg/3 per day; 21-day cycles up to 8 cycles
Vorinostat	II	Relapsed or refractory Hodgkin’s lymphoma	25 patients	400 mg/day; 14 days of 21-day cycle	SAEs, 7/25; death, 2/25; lack of efficacy, 11/25; CR, 0/25; PR, 1/25; NO response, 24/25; median PFS, 4.5 months
Romidepsin	II	Relapsed or refractory non-Hodgkin’s lymphoma	9 patients	13 mg/m^2 intravenous injection over 4 hours on days 1, 8, and 15	PR, 11.11%; median PFS, 4 months; median OS, 20 months; no safety issue
Panobinostat	II	Renal cell carcinoma	20 patients	45 mg/day, twice weekly	Median PFS, 1.7 months; SAEs, 6/30; no safety issue
Belinostat	II	Thymoma, thymic carcinoma	41 patients	1000 mg daily; 5 days every 3 weeks	PR, 2/25 thymoma patients; 0/16 thymic patients; SAEs, 6/41
Combination therapies
Vorinostat/bexarotene	I	Advanced cutaneous T-cell lymphoma	6 cohorts 23 patients total	Vorinostat 200–400 mg/day, bexarotene 150–300 mg/day orally, 3 times a week	SAES, 2/23; response rate, 4/23
Vorinostat/tamoxifen	II	Breast cancer	43 patients	Vorinostat 400 mg/day/3 out of 4 weeks, tamoxifen 20 mg daily	OR, 8/43; TTP, 10.3 months; SAEs, 4/43; safety issue, yes
Vorinostat/bortezomib	I	Advanced multiple myeloma	6 cohorts 34 patients total	Vorinostat 200–400 mg/2 capsules daily/21-day cycles, bortezomib 0.7–1.3 mg/4 injections per 21-day cycle	3 discontinued due to SAEs
Vorinostat/erlotinib	I/II	Relapsed/refractory non-small-cell lung cancer	2 cohorts 16 patients total	Vorinostat 200 mg/day/3 days per week, erlotinib 150 mg/day	SAEs, 5/16; discontinued due to progressive disease, 9/16; terminated due to lack of efficacy and overall tolerance in patients
Vorinostat/pemetrexed and cisplatin	I	Advanced solid cancers	4 cohorts 52 total patients	Vorinostat 200–400 mg/1 or 2 capsules daily/14 days out of 3 weeks, pemetrexed + cisplatin or pemetrexed	SAEs, 20/54 patients; progressive disease, 24/54 patients; safety and tolerability, 24/52 patients
Vorinostat/decitabine	I	Leukemia, myelocytic, acute myelodysplastic syndromes	6 cohorts 71 patients total	Vorinostat 400 mg/daily/3 days out of 21-day cycle, decitabine 20 mg daily, 5 days out of 28-day cycle	SAEs, 15/71; lack of efficacy, 6/71; progressive disease, 42/71
Vorinostat/trastuzumab	I/II	Breast cancer	16 patients	Vorinostat 200 mg twice daily/14 days out of 21-day cycle, trastuzumab 6 mg/kg daily, 1 day out of 21-day cycle	Response rate, 0/10; TTP, 1.5 months; SAEs, 4/16

Abbreviations: PR, partial response; PFS, progression-free survival; OS, overall survival; OR, objective response; TTP, time to progression; SAEs, serious adverse effects.