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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Cyclic peptides, also referred as ‘macrocyclic’ compounds, inhibit HDAC by interacting with the outer rim of the enzyme (Mwakwari et al., 2010). These cyclic compounds usually contain complex cap-groups which bind to the HDAC’s outer rim regions, thereby inhibiting the enzyme activity with more potency and isoform selectivity (Maolanon et al., 2016). Based on their macrocyclic moieties, these HDACi are subdivided into: (a) cyclic peptides; and (b) depsipeptides. The first class contains a mixture of L- and D-amino acids and cyclic amino acids such as proline or pipecolic acid (Mwakwari et al., 2010). Examples of cyclic peptides are trapoxin-A and trapoxin-B, apicidin (a fungal metabolite from fusarium species), azumamide (isolated from Mycale izuensis) and HC-toxin (Mwakwari et al., 2010).
Ultraviolet and Light Absorption Spectrometry
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Zoltan M. Dinya, Ferenc J. Sztaricskai
Depsipeptides represent a quite new type in the family of peptide antibiotics, the molecules of which are built from hydroxy and amino acids with amide and ester linkages constructing linear or cyclic structures. A further distribution inside this group can be made on the basis of the following structural feature [117]: whether the molecules are built by regular alteration of α-hydroxy and α-amino acids (enniantines, validomycin, and amidomycin, among others) or from an irregular sequence of both α- and β-hydroxy acids (such as sporidesmolides, serratomolide, and esperin) or of β- or λ-hydroxy-α-amino acids, containing both functional groups (including etamycin, staphylomycins, echiomycin, and osterogricins).
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Among the first cyclic peptides were the trapoxins, fungal products isolated in 1990 from the culture broth of Helicoma ambiens (66). These compounds exhibit both potent in vitro cytotoxicity and the ability to cause the accumulation of acetylated histones (67). Depsipeptide (romidepsin, formerly known as FK228, FR901228) has emerged as a structurally similar natural product. It was first isolated from a broth culture of chromobacterium violaceum in 1994, shortly after demonstrating antitumor activity in vitro and in vivo in various malignancies (68,69). In fact, Piekarz and Bates made one of the first reports describing the activity of an HDAC inhibitor in T-cell lymphoma in 2001. This publication was among the first to report responses to depsipeptide in patients with drug-resistant CTCL. Patients with advanced or refractory disease received romidepsin as a four-hour infusion on days 1 and 5 of a 21-day cycle, with the maximum tolerated dose (MTD) being 24.9 mg/m2. DLTs included nausea, vomiting, thrombocytopenia, and atrial fibrillation (70,71).
Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma
Published in Expert Opinion on Pharmacotherapy, 2021
Anna Wolska-Washer, Piotr Smolewski, Tadeusz Robak
Romidepsin (depsipeptide, Istodax®, Celgene) was approved by the FDA in 2011 for the treatment of PTCL in patients who have received at least one prior therapy [28]. The approval was based on two phase 2 trials. The first one included 130 patients who were relapsed or refractory to at least one prior systemic therapy [29]. The ORR was 25%, including 15% with CR, and the median duration of response (DOR) was 17 months. The responses were durable in patients demonstrating CR, with 89% of patients still not experiencing progressive disease at a median follow-up of 13.4 months. The most common serious adverse events (AEs) were thrombocytopenia in 24%, neutropenia in 20% and infections in 19% of patients. An extended follow-up revealed that a median DOR for patients with CR was not reached, and overall the patients showed sustained responses with a median DOR of 28 months (range from 1 to over 48 months) [30]. The second trial involved 47 patients with a median of three prior therapies [31]. The ORR was 38% with 17.7% of CRs and 20% of PRs. The median DOR was 8.9 months (range 2–74 months). However, romidepsin did not meet the EMA requirements for a conditional marketing authorization [32].
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
The enzyme histone deacetylase (HDAC) is involved in the remodeling of chromatin and it plays an important role in the epigenetic regulation of gene expression. In preclinical studies, inhibition of HDACs shows potential antitumor activity with pleiotropic effects, including gene regulation, cell cycle arrest, anti-angiogenesis, and activation of apoptosis. Several HDAC inhibitors, such as romidepsin, vorinostat, and belinostat, have already been approved by the US FDA for the treatment of T-cell lymphomas. Romidepsin (FR901228) is a bicyclic depsipeptide that was discovered by a Japanese investigator from cultures of Chromobacterium violaceum isolated from a sample of Japanese soil [16]. It was initially expected to be an antimicrobial agent, but preclinical studies revealed its potent inhibitory activity against HDAC class I enzymes, and prominent antitumor activities against murine and human tumor cell lines both in vitro and in vivo [17].
Cancer prevention and treatment using combination therapy with natural compounds
Published in Expert Review of Clinical Pharmacology, 2020
Romidepsin belongs to a class of peptides known as depsipeptides. The agent was initially obtained from the bacterium Chromobacterium violaceus, though now it is synthesized in 14 chemical steps. It works by blocking histone deacetylases, thereby inducing apoptosis [161]. The compound is a pentapeptide with one or more of their normal peptide amide bonds replaced with an ester bond. It was isolated by Fujisawa Pharmaceuticals as part of an ongoing search for new antibiotics. While romidepsin has little antibiotic activity, it is cytotoxic to cancer cells [162].