Table 5.

Current HDACi repurposed drugs with applications in cancer therapy [*modified from Moreira-Silva et al. (9)].

Class	Compound	First indication	Epigenetic target	Drug-target interaction	Cancer model/New indication	Key features in mechanism	References
HDAC inhibitors
Acid	Valproate (VPA)	Antiepileptic	HDAC class I and HDAC2	Inhibits HDAC class I activity by binding to the catalytic site and promotes proteasomal degradation of HDAC2.	Melanoma treatment	Potentiates karenitecin-induced apoptosis in multiple melanoma cell lines and on xenografted mice, however, fails to enhance chemotherapy effects on dacarbazine plus interferon-α-treated melanoma patients.	(197, 198)
					Colon Cancer cells	Reduces relative HDAC2 mRNA expression, preventing cell colony formation and migration.	(199)
					Non-small Cell Lung Cancer cells	Increases major histocompatibility complex (MHC) class I chain-related protein A (MICA) expression and sensitizes cancer cells to γδ T-cell-mediated killing.	(200)
					Colon Cancer Tumor cells	Synergistically reduces viability of cancer cells in combination with mytomicin C.	(201)
					Ovarian Cancer cells	Upregulates WWOX and P27 genes and interferes with the cell cycle by promoting apoptosis and inhibiting cell proliferation, both in vitro and in vivo.	(202)
Phenolic	Artemisin	Antimalarial	HDAC1, HDAC2 and HDAC6	Not described	Breast Cancer cells	Inhibits cell proliferation, cell migration, invasion and induces apoptosis. Also inhibits HDAC 1, 2, 6 and up-regulates BRCA1, 2/Ras/ERα/ERβ/PR/Her expression	(203)
	Ginseng	Nutraceutical (not approved)	HDAC	Not described	Lung Carcinoma cells	Inhibits HDAC activity, increases p21 expression and induces apoptosis.	(204)
	HC toxin	Natural Compound antiprotozoal (not approved);	HDAC	Not described	Breast Cancer cells	Inhibits cell proliferation and induces cell cycle arrest at G2/M and apoptosis in a dose-dependent manner.	(205)
					Neuroblastoma Cells	Induces cell cycle arrest and apoptosis, induces neuronal differentiation and inhibits invasive growth. Increases p-RB, p15, p16, p21, p27 expression, and reactivates the RB tumor suppressor pathway. Also induces H4 acetylation while inhibits HDAC activity	(206)
	Psammaplin A (PsA)	Enzimatic inhibitor Bromotyrosine Natural Compound (not approved);	HDAC III (SIRT1)	Inhibits HDAC activity via the coordination of zinc ion in catalytic pocket of HDAC with sulfhydryl group activated by a reducing agent.	Ovarian Cancer cells, Colon Cancer cells and Cervical Cancer cells	Displays significant cytotoxic activity, inhibits cell proliferation and upregulates expression of tumor-suppressor gene gelsolin in a dose-dependent manner	(207, 208)
					Endometrial Cancer cells	Inhibits cell proliferation, significantly induces H3 and H4 acetylation, upregulates expression of cyclin-dependent kinase inhibitor, p21, and downregulates expression of pRb, cyclins, and CDKs, promoting cell cycle arrest.	(209)
					Breast Cancer cells	Inhibits proliferation induces cell cycle arrest at G2/M and reduces SIRT1 activity protein expression levels and reduces nuclear SIRT1 levels. Increases p53 acetylation (target of SIRT1) and increases DRAM expression	(208, 210)
Fatty acid	Sodium Butyrate	Anti‐inflammatory	HDAC1	Not described	Gastric Cancer cells	Increases DAPK expression in human gastric cancer cells and this expression prompted apoptosis by decreasing FAK levels. Suggesting that DAPK expression prompts apoptosis by reducing the FAK protein level. Induce demethylation of the SFRP gene promoter	(211)
					Breast Cancer cells	Decreases cell proliferation induces cell cycle arrest at G1/G2 and decreases nuclear expression of DNA DSB repair proteins induced by etoposide (BRCA1 RAD51, ATM). Also increases H4 acetylation.	(212)
					Prostate Cancer cells	Inhibits HDAC1, 3 activity and induces H3, H4 acetylation, leading to hyperacetylation of H3 and H4 on the p21 promoter region, thus increasing p21 expression. Also induces cell cycle arrest, promoting apoptosis.	(213)
Hydroxamic acid	Trichostatin A (TSA)	Antifungal	HDAC class I, II and SIRT6	Hydroxamate. Pan-HDAC inhibitor, that obtain the binding energy associated with the strength of inhibition is derived from the bidentate chelation of hydroxamate	Breast Cancer cells	Decreases cell proliferation, inhibits HDAC activity, thus increases H4 hyperacetylation And increases ER acetylation and anti-tumor activity	(214)
					Myeloid Leukemia (AML) cells	Inhibits HDAC activity leds to histone hyperacetylation. Increases H4 acetylation and reduces Myc expression ZNF278 (Myc’s coactivator), NM1, HOXB6 and MKRN3	(215)
					Esophageal Squamous Carcinoma cells	Decreases cell proliferation, induces cell cycle arrest at G1, down-regulates cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways, and increases H4 acetylation levels	(216)
					Prostate Cancer cells	Increases apoptosis induces p21 expression and represses TMPRSS2-ERG expression AND affect acetylation status of p53 by inhibiting HDAC activity. Disrupts the epidermal growth factor receptor (EGFR),-STAT3 pathway, thus, inhibits proliferation in CRPC cells. Increases H4K16acetylation and promotes gene transcription, moreover decreases phospho-Akt pathway	(217, 218)
					Pancreatic Cancer cells	Restores cellular differentiation, reduces proliferation and restores p21 expression. Increases NDGR1 mRNA expression, also increases hypoxic responses	(219)
					Colon Cancer cells	Decreases cell growth and promotes apoptosis, down-regulates DNMT1 and HDAC1 expression, increasing p21, p27 and p57 expression	(220)
					Hepatocellular Carcinoma cells	Increases H3K9 and H3K27 acetylation and increases SERCA3 mRNA expression levels and promote ATP2A3 gene expression	(221)
	Vorinostat (SAHA)	Psoriasis disease treatmenr	HDAC class I, II and IV	inhibits HDAC activity by binding to the pocket of the catalytic site processes by removing acetyl groups from proteins	Advanced Prostate Cancer treatment	In a phase II trial, it was associated with significant toxicities limiting efficacy assessment in patients with disease progression on one prior chemotherapy	(222, 223)
					Follicular and Mantle Cell Lymphoma treatment	In a phase I trial in follicular and mantle cell lymphomaoral vorinostat was well tolerated up to 200mg bd for 14 consecutive days every 3 weeks in Japanese patients with NHL. Shown favorable results	(224)
	Panobinostat	HDACi multiple myeloma	HDAC	Pan-HDAC inhibitor, blocks the enzymatic activity of HDAC	Multiple myeloma treatment	It has improved progression-free survival when combined with bortezomib and dexamethasone in patients with relapsed multiple myeloma who previously received bortezomib and an immunomodulatory agent	(225)
Depsipeptide	Burkholdacs A	Pathogen bacteria (not approved)	HDAC1, HDAC6	Inhibits HDAC catalytic activity by reduction of the disulfide bond which generates a free thiol group that interacts with the catalytic site in HDACs.	Brain Cancer cells	In at least six cancer cell lines, it has shown superior HDACi activity over Ramidopsine (approved HDACi). Burkholdacs A presents more affinity for HDAC1 and was determined to be superior than B with respect to its HDAC1 inhibitory activity and isoform selectivity toward HDAC1 over HDAC6 and antiproliferative activity.	(226)
					Colon Cancer cells
					Lung Cancer cells
					Ovary Cancer cells
					Stomach Cancer cells
					Prostate Cancer cells
	Thailandepsin (Burkholdacs B)	Pathogen bacteria (not approved)	HDAC6		Cervical Cancer cells		(226, 227)
					Breast Cancer cells		(227)
	Spiruchostatin A	Pathogen bacteria (not approved)	HDAC1 and HDAC6	Structural similarity with HDAC inhibitor FK228 (Romidepsin) which interacts with the active-site zinc in its reduced form, preventing it from interacting with substrate.	Breast Cancer cells	Increases acetylation levels of specific lysine residues of histones H3 and H4.	(228, 229)
					Ovarian Cancer cells
					Brain Cancer cells
					Colon Cancer cells
	Apicidin	Antiprotozoal for Malaria	HDAC3, HDAC4 and HDAC8	Cyclic tripeptide that chelate the active site zinc ion through the terminal carbonyl, hydroxy and/or amino functional groups	Promyelocytic Leukemia treatment	Inhibits cell proliferation an cycle arrest, promoting cell death. Increases H4 acetylation and inhibits HDAC activity, thus increases p21 expression.	(230)
					Lung, Colon and Pancreatic Cancer cells	Induces DNA demethylation via HMT suppression, reduces HP1 and DNMT1 recruitment to genes’ promoter and induces p16, SALL3, and GATA4 expression. Also, decreases SUV39 and G9a expression in lung cancer cell lines.	(231)
					Cervical Cancer cells	Induces demethylation of CpG islands of the 1st exon of the PDH2 gene AND induces PHD2 and p21 gene expression and inhibits cell proliferation.	(232)
					Breast Cancer cells	Increases H3 and H4 acetylation and reduces ERalfa and ERb expression. Increases p21 and p27 expression and reduces cyclin D1 and cyclin E expression. Also reduces cell proliferation, thus promotig apoptosis.	(233)
					Endometrial Cancer cells	Increases H3 acetylation and reduces HDAC3, 4 expression, decreases cell proliferation and induces apoptosis.	(217)
					Ovarian Cancer cells	Decreases HDAC activity, reduces HDAC4 expression and blocks cell migration and invasion. Increases H3 and H4 acetylation and increases RECK expression through reducting the binding of HDAC4 to the Sp1 of its promoter, while reduces MMP-2 expression.	(234)
					Oral Squamous Cell Carcinoma cells	Inhibits cell growth, proliferation and reduces HDAC8 expression. Induces apoptosis and autophagy AND increases H4 acetylation.	(235)
	Platycodi	Nutraceutical (not approved)	HDAC	Not described	Lung Carcinoma cells	Inhibits HDAC enzymatic activity and induces the expression of p21. Stimulates cell death and inhibits cell proliferation.	(204)