TABLE 1.

Most common clinically used histone deacetylase inhibitors that have been approved by the FDA or are currently undergoing clinical trials for the treatment of cancer.

HDAC inhibitor	HDAC class	Maximum phase of therapy	Cancer type	Status	FDA approval	DNA damage impact: Proteins regulated or involved/pathway impact/cellular response
Romidepsin	Cyclic tetrapeptide	Phase III	Peripheral T cell lymphoma	Active, not recruiting	No	DNA damage and apoptotic cell death through caspase activation; accumulation of DNA-RNA hybrids (R-loops); radiosensitiser; activation of ATM pathway, increased production of reactive oxygen species (ROS), decreased mitochondrial membrane potential Valdez et al., (2018); Miles et al., (2019); Paillas et al., (2020); Rossetti et al., (2021); Safari et al., (2021)
		Phase II	Cutaneous T-cell lymphoma; peripheral T-cell lymphoma; T-cell non-Hodgkin lymphoma	Completed	Yes
		Phase I/II	Relapsed/refractory T-cell lymphoma; peripheral T-cell lymphoma; relapsed/refractory lymphoid malignancies; multiple myeloma, non- Hodgkin’s lymphoma; recurrent or metastatic triple negative breast cancer	Active, not recruiting	No
Panobinostat	Hydroxamates	Phase III	Multiple myeloma	Completed	Yes	Pleiotropic antitumour effects and autophagy; induces clastogenicity, aneugenicity, oxidative damages and hypomethylation; increased G2/M arrest and production of ROS, enhanced proton-induced DNA damage A. Wilson et al., (2020); Choi et al., (2021); Al-Hamamah et al., (2019); Medon et al., (2017)
		Phase III	Acute myeloid leukemia; myelodysplastic syndromes	Completed	No
		Phase II	Multiple myeloma; recurrent plasma cell myeloma; refractory/relapsed multiple myeloma; relapsed/refractory non-Hodgkin lymphoma; diffuse intrinsic pontine glioma	Active, not recruiting	No
Mocetinostat	Benzamide	Phase II	Non-small cell lung carcinoma	Active, not recruiting	No	Potentially regulates RAD51 through HDAC2 in some cancers; maintains chromatin state; chemosensitizer; tumor suppression; increases tumor antigen presentation; cell cycle progression; suppresses cell proliferation; induces apoptosis through the upregulation of miR-31 (pro-apoptotic microRNA) (Briere et al., (2018); Q. Zhang et al., (2016b; Mondal et al., (2020); Headley et al., (2019); Shan et al., (2017); Yan and Efferth (2020)
		Phase I/II	Hodgkin lymphoma; lymphoma; relapsed/refractory hodgkin lymphoma; relapsed and refractory diffuse large B-cell lymphoma and follicular lymphoma	Active, not recruiting	No
MS-275	Miscellaneous	Phase III	Advanced/metastatic breast cancer	Active, not recruiting	No	Inhibits RAD51/FANCD2 mediated HR; increases radiosensitization by prolongation of γH2AX Yao et al., (2018); Christmann and Kaina (2019); Kaina and Christmann (2019)
		Phase II	Renal cell carcinoma; male breast carcinoma, recurrent breast carcinoma; endometrial endometrioid adenocarcinoma; cholangiocarcinoma and pancreatic cancer; metastatic pancreatic cancer; metastatic uveal melanoma; bladder cancer; advanced or recurrent breast cancer	Active, not recruiting	No
		Phase I/II	Epithelial ovarian cancer; peritoneal cancer; fallopian tube cancer; CNS tumor; solid tumor; non-small cell lung cancer; melanoma; mismatch repair-proficient colorectal cancer; clear renal cell carcinoma; metastatic kidney carcinoma; stage III, IV renal cell cancer; breast neoplasm	Active, not recruiting	No
Abexinostat	Hydroxamates	Phase III	Renal cell carcinoma	Active, not recruiting	No	Regulates RAD51 (Kashyap et al., (2020)
		Phase II	Relapsed/refractory follicular lymphoma	Active, not recruiting	No
Belinostat	Hydroxamates	Phase II	Peripheral T-cell lymphoma	Completed	Yes	Upregulates the expression of several genes in DNA damage pathway (PARP1, Gadd45a, Mpg); downregulates the expression of several genes involved in DNA damage pathway (Cdc25c, RAD 18, 51, 9, 1, TRP53, XRCC1); radiosensitizing through the induction of oxidative stress and DNA damage; interferes with mitotic spindle assembly; promotes stem cell differentiation and inhibits MYC pathways (García-Giménez et al.,; To et al., (2017); F. Chi et al., (2021; Marijon et al., (2018); Attia et al., (2018)
		Phase II	Unresectable/metastatic conventional chondrosarcoma; glioblastoma multiform of brain; T-cell leukemia-lymphoma	Active, not recruiting	No
Valproic acid	Short-chain fatty acid	Phase IV	Seizure treatment in glioma	Completed	Yes	Upregulates gadd45a; radiosensitizer via increase of γH2AX phosphorylation; alters cell proliferation, cell survival, cell migration and hormone receptor expression; increases cell cycle arrest by increasing the expression of cyclin dependent kinase inhibitor (CDKN1A) Jang et al. (2020); Gao et al., (2020); Yan et al., (2021); Bhatti et al., (2021); Ding et al., (2020)
		Phase II	High-grade glioma; myelodysplastic syndromes	Active, not recruiting	No
		Phase I/II	Solid tumors; acute myeloid leukemia	Active, not recruiting	No
Vorinostat	Hydroxamates	Phase III	Multiple myeloma; relapsed/refractory cutaneous T-cell lymphoma	Active, not recruiting	No	Downregulates the expression of genes involved in DNA repair pathway (BIRP1, CDC25C, RAD proteins, TRP53, XRCC1); upregulates mRNA transcripts of repair genes implicated in DNA damage (Gadd45a, PARP1, BAX); induces chromosomal aberrations, oxidative damages, apoptosis and hypomethylation; decreases cellular viability and ROS (Singh et al., (2021); Sher et al., (2020); Zhang et al., (2020); Attia et al., (2020)
		Phase II	Cutaneous T-cell lymphoma	Completed	Yes
			Breast cancer; neuroblastoma; adenomas in Cushing’s disease; cutaneous T-cell lymphoma/mycosis fungoides; myelodysplastic syndromes or chronic myelomonocytic leukemia	Active, not recruiting	No
		Phase II/III	High grade glioma	Active, not recruiting	No
		Phase I/II	Recurrent squamous cell head and neck cancer or salivary gland cancer; melanoma, skin neoplasms; multiple myeloma; advanced sarcoma; diffuse large B-cell lymphoma (stage II, III or IV); glioblastoma; glioblastoma multiforme; HIV-related diffuse large B-cell non-hodgkin lymphoma; acute myeloid leukemia in remission; myelodysplastic syndromes or acute myeloid leukemia	Active, not recruiting	No
Nicotinamide	Sirtuins inhibitors	Phase III	Head and neck cancer; skin cancer	Completed	Yes	Represses genes involved in DNA damage and repair (FANCD2, BRCA1, RAD51; increases levels of phosphorylated DDR markers (γH2AX, pChk1 and p53) leading to cellular sensitivity (Pillay et al., (2021); Ogino et al., (2019); Magalhaes et al., (2021); Singh et al., (2021)
		Phase II	Non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma; breast cancer metastatic, platinum resistant recurrent ovarian cancer; metastatic lung carcinoma; chronic myeloid leukemia	Active, not recruiting	No
		Phase II/III	Non-small cell lung carcinoma	Active, not recruiting	No

Source: U.S. National Library of Medicine, U.S. Food and Drug Administration, NIH Clinical Trial database: www.clinicaltrials.gov