TABLE-1: FDA Approved Drugs of HDAC Inhibitors

Medication	Route of Administration	HDAC Classes Inhibitor	Indication	Response Rates	Side Effects
Romidepsin (FDA Approved)	Intravenous	Class l (slight inhibitions of class ll)	Cutaneous T-cell lymphoma	34%-35%	Nausea, increased risk infection, fatigue, thrombocytopenia, QTc, prolongation(rare)
			Peripheral T-cell lymphoma	25%-38%
Vorinostat (FDA Approved)	Oral	Class l and ll	Cutaneous T-cell lymphoma	24.2%-36%	Diarrhoea, fatigue, nausea, anorexia, Thrombocytopenia and anaemia
Panobinostat (FDA Approved)	Oral	Class l, ll, lV	Cutaneous T-cell lymphoma	20%	Anorexia, nausea, fatigue, diarrhoea, thrombocytopenia and anaemia
			Hodgkin lymphoma	22%-24%
Belinostat (FDA Approved)	Intravenous	Pan- inhibitor	Cutaneous T-cell lymphoma	14%	Nausea, vomiting, lethargy, fatigue, constipation, flushing and diarrhoea
			Peripheral T-cell lymphoma	26%

TABLE-2: Brief study of HDAC Inhibitors:

Trade Name	Chemical Names	FDA Approved Indication	Classificaton	Clincal Trials
Zolinza	Vorinostat SAHA	CTCL	Hydroxamate	Multiple myeloma Mesothelioma Neuroblastoma Glioblastoma Non-Hodgkin lymphoma
Isodax	Romidepsin FK228	CTCL PTCL	Cyclic peptide	Multiple myeloma Breast cancer Lymphoma Sarcoma Small cell lung cancer
Beleodaq	Belinostat PXD101	Multiple melanoma	Hydroxamate	CUP Ovarian cancer Hepatocarcinoma Soft tissues sarcoma NSCLC AML and MDS
Farydak	Panobinostat LBH-589	CTCL	Hydroxamate	Multiple myeloma CML Hodgkin lymphoma Metastatic melanoma Prostate cancer

HISTONE DEACETYLASE:

Histone deacetylase constitute a class of targeted anticancer agents that inhibit histone deacetylase and effect chromatin modulation through altered binding of transcription co-activator of non-histone proteins. HDACs repress two genes involved in DNA synthesis, CTP synthase and thymidylate synthetase [7]. HDACs are categorised as being zinc dependent or nicotinamide adenine dinucleotide (NAD) [8]. HDACs are grouped into four major classes. Class 1 consist of HDACs 1,2,3and8, class 2 consist of HDACs 4,5,6,7and 9 and class 3 consist of sirtuins 1-7 (SIRT) and class 4 consist of only HDACs 11 [9].

Recently the pattern of HDACs enzyme expression was examined in a panel of well characterised lymphoid cell lines and tissue section from primary lymphoid tumours.

HISTONE DEACETYLASE INHIBITORS:

HDACs regulate a variety of cell functions several structurally distinct classes of HDACs inhibitors have been developed. Clinically approved Histone deacetylase inhibitors are Vorinostat, Romidepsin, Belinostat, Panobinostat [10]. All types of Histone deacetylase inhibitors are tabulated in Table 2.

VORINOSTAT:

The first drug approved by USFDA in OCT 2006 for CTCL treatment. Vorinostat also known as SAHA or zolinza. Vorinostat inhibits HDAC class 1 and class 2 and it shown to have potent antiproliferative activity in Hodgkin lymphoma derived cell.^[11] Vorinostat is another form of anticancer agent HDAC inhibitor and it has been approved for the treatment especially for CTCL^[12]. The response result shown as 30% only the Phase 1 study have indicated that Vorinostat monotherapy and Phase 2 study in patient with diffuse large B-cell lymphoma i.e. Combination therapy. Vorinostat is also being studied in various cancer agent in single therapeutic such as leukaemia and lung cancer, multiple myeloma, MDS, breast, pelvic, prostate cancer^[13].

ROMIDEPSIN:

Romidepsin is a bicyclicdepsipeptide antibiotic i.e. isolated from the bacterium also Chromobacterium violaceum. Romidepsin also known as FK228, FR901228, DESIPEPTIDE or ISTODAX, was the second drug approved by USFDA in November 2009 for CTCL. It is structurally unique potent bicyclic class 1 HDAC^[14]. Romidepsin has been shown to induce cell differentiation, cell cycle arrest and apoptosis. Romidepsin severs as a prodrug i.e. activated only after uptake into cells. Romidepsin concentration of drug arrest the growth as opposed to apoptosis it is predominant response in cell lines. After response result shown histone deacetylase inhibitor in CTCL for Romidepsin were 34%-35%^[15]. On phase II trial, Romidepsin was administered by IV Infusion to 96 CTCL patients. However, side effects were reported such as nausea, vomiting, diarrhoea, myelotoxicity, asthenia and cardiac toxicity. Currently, 34 ongoing clinical trials are studying the effect of Romidepsin as a single agent on many other cancers such as leukaemia, melanoma, and bladder, colorectal, breast, ovarian and prostate cancers. Also, the FDA as cautioned that Romidepsin may cause changes in an electrocardiogram and as suggested that periodic tests be conducted to monitor the electrolytes of patients undergoing treatment with Romidepsin.

BELINOSTAT:

The third drug approved by USFDA in July 2014 for relapsed or refractory PTCL was Belinostat. Belinostat’s efficacy as monotherapy was the basis for the first pivotal phase I trial of this agent to treat relapsed or refractory peripheral T-cell lymphoma. Over all response rate is 26% for relapsed or refractory PTCL^[16]. However adverse events were reported, mainly fatigue, nausea, vomiting, diarrhoea, constipation, phlebitis, headache and dyspnoea. Belinostat is the only HDAC inhibitor in clinical development that has multiple potential routs of administration, including intravenous administration, continuous intravenous infusion and oral administration.

PANOBINOSTAT:

Panobinostat or Faridak was the fourth drug approved by USFDA in February 2015 for the treatment of multiple myelomas. Panobinostat is highly potent pan-HDAC inhibitor that has shown antitumor activity in patients with Hodgkin lymphoma, multiple myeloma and acute myeloid leukaemia. Panobinostat has shown an objective response of 27%. However, it induces diarrhoea and cardiac toxicities. It inhibits class I, II and IV HDACs^{[17] [18]}_. Panobinostat is being studied in 50 clinical trials as a single agent for the treatment of other cancers such as CTCL, AML, Hodgkin’s lymphoma, MDS, thyroid carcinoma and colorectal and prostate cancers ^[19]_.

CONCLUSION:

The effects of HDAC inhibitors on proteins which plays a major role in regulating numerous cell pathways make these agents attractive as potential anticancer therapeutics. Romidepsin is potent inhibitors offers a promising new treatment for a disease with few existing therapies. We also found Romidepsin to be a more effective inducer of apoptosis in the annexin assay than Vorinostat. From this study emerged recognition of two distinct HDACs effects. Essentially the activity of Romidepsin, coupled with the unmet medical need in CTCL, were persuasive enough arguments to move the drug forward. Romidepsin and Vorinostat are HDAC inhibitor used for the treatment for CTCL. Hematologic parameters should be monitored in patients receiving Romidepsin, whereas patients who are predisposed to QTc prolongation should be carefully monitored while receiving Vorinostat. Vorinostat is available in 100mg capsules and Romidepsin is administered by IV infusion over 4 hours. Vorinostat and Romidepsin may be beneficial for the treatment of CTCL. Several preclinical and clinical studies have indicated that HDAC inhibitors potentiate the efficacy of a variety of chemotherapeutic drugs. Thus, in the future, it will be important to consider combining several new agents and HDAC inhibitors to build new non-chemotherapy-based regimens that will maintain a high cure rate and it will also reduce treatment-related toxicity.

ABBREVIATIONS:

HDAC	Histone deacetylase
CTCL	Cutaneous t-cell lymphoma
PTCL	Peripheral T-cell lymphoma
HDI	Histone deacetylase inhibitor
NAD	Nicotinamide adenine dinucleotide

ACKNOWLEDGMENT:

The authors are thankful to Dr. M.G.R. Educational and Research Institute and its management for providing research facilities and encouragement.

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Received on 01.09.2019 Modified on 21.10.2019

Research J. Pharm. and Tech 2020; 13(6): 2963-2965.

DOI: 10.5958/0974-360X.2020.00524.7

17. Andrew Bodiford, Megan Bodge, Mahsa S Talbott, Nishitha M Reddy. Profile of belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma., 2014; 7:1971-1977.

17. Andrew Bodiford,Megan Bodge, Mahsa S Talbott, Nishitha M Reddy. Profile of belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma., 2014; 7:1971-1977.