Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Namrita Lall in Medicinal Plants for Cosmetics, Health and Diseases, 2022
Even though several naturally occurring and synthetic HDAC inhibitors have been developed, only very few agents have reached the clinical trials stage. Even among those which have reached clinical trials stage, many have failed to hit the market due to various toxicities and poor efficacy in inhibiting the disease symptoms at the dose tested. For example, SAHA (Vorinostat) is an FDA-approved drug for treating T-cell lymphoma. However, when administered at a dose of 300 mg/day, the patients have reported diarrhea, thrombocytopenia, nausea and pyrexia. Adverse events such as cardio-toxicity were reported when tested at a dose of 400 mg/day (Duvic and Vu, 2007). Similarly, systemic toxic effects have been reported for other FDA-approved HDAC inhibitors, which include Belinostat, Panobinostat, etc. (Allen and Lechowicz, 2018). Therefore, care must be executed when recommending HDAC inhibitors for treatment. Recent studies have focused on reducing the toxicity of HDAC inhibitors by: (a) combining with other pharmacological agents or other treatment methods such as radiation therapy, surgery etc.; (b) developing targeted nanodrug formulations; and (c) antibody conjugates. However, further studies are currently required to determine the safety and efficacy of these methods or formulations.
Clinical Trials
Abhaya Indrayan in Research Methods for Medical Graduates, 2019
Sometimes a regimen is approved on the basis of a single-arm trial. Remember that such a trial does not establish superiority or equivalence. Belinostat was approved for relapsed peripheral T-cell lymphoma on the basis of such an uncontrolled trial [22]. Even in RCTs, the effect size may be statistically significant due to a large sample but actually too small to have clinical significance. Some trials look at surrogates such as progression-free survival where quality of life is possibly more relevant. Just beware of such fallacies and take steps to avoid them.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Belinostat is a histone deacetylase inhibitor (HDI) approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) (1000 mg/m2 i.v. daily on days 1–5 of a 21-day cycle). Dose reductions of 25% (750 mg/m2) are recommended for hematologic and nonhematologic toxicities, including neutropenia and thrombocytopenia (nadir absolute neutrophil count<0.5 × 109/L or platelet count < 25 × 109/L). Since UGT1A1 catalyzes the primary metabolic pathway involved in belinostat elimination [91, 92], variability in UGT1A1 metabolic phenotypes are important considerations in belinostat therapy. Particularly, polymorphisms that limit belinostat metabolism through UGT1A1 result in significant pharmacokinetic variability [93–95]. The starting dose of belinostat in patients homozygous for the UGT1A1*28 allele should be reduced to 750 mg/m2. Co-therapy with strong UGT1A1 inducers and inhibitors is also of significant clinical concern. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206256lbl.pdf) Albeit, formal drug-drug interaction (DDI) studies have not been conducted on belinostat at this time, but the irinotecan literature (summarized above) may be useful in selecting therapies that do not interact with belinostat. Irinotecan and belinostat coadministered to human liver microsomes resulted in inhibition of the metabolism of both drugs, and this combination has a very high potential for clinically significant DDIs due to pharmacokinetic variability [93] and overlap in the mechanism of action for these agents [96]. While the influence of pharmacogene variation on belinostat requires additional study, polymorphic variation in UGT1A1 (particularly that of UGT1A1*28/*28 and UGT1A1*6/*6, UGT1A1*60/*60), bilirubin processing disorder, and co-therapies with UGT1A1 substrates should be considered.
An update on the emerging approaches for histone deacetylase (HDAC) inhibitor drug discovery and future perspectives
Published in Expert Opinion on Drug Discovery, 2021
Along with further research on HDACs, HDAC inhibitors have attracted many attentions in recent decades. So far there have been more than 30 HDAC inhibitors investigated in clinic trials and have achieved five approvals (Figure 1)[24]. Vorinostat (compound 1) is the first FDA-approved HDAC inhibitor in 2006 to treat cutaneous T-cell lymphoma[25]. In 2009, Romidepsin (compound 2) was received FDA approval as cutaneous T-cell lymphoma treatment as well. In 2014, Belinostat (compound 3) is the third HDAC inhibitor to receive FDA approval for T-cell lymphoma treatment[26]. Panobinostat (compound 4) received approval by both the FDA and the EMA to treat relapsed or refractory multiple myeloma[27]. Lastly, in 2015, Tucidinostat (compound 5) was approved by the CFDA as treatment of peripheral T-cell lymphoma.
A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma
Published in Expert Opinion on Drug Safety, 2019
Guldane Cengiz Seval, Meral Beksac
Belinostat (PXD101) is a novel hydroxamic acid HDAC inhibitor with potent anti-proliferative and HDAC inhibitory activity in vitro. Belinostat has growth-inhibitory and pro-apoptotic activity in a variety of human tumor cell lines (including myeloma, lymphoma, and leukemia lines) at submicromolar concentrations. In vivo, belinostat inhibits growth in human tumor xenografts without apparent toxicity to the host mice. Growth inhibition in vitro and in vivo is concomitant with a marked increase in the level of acetylation of histone proteins H3 and H4. This results in a modification of the expression of cell-cycle and survival regulatory proteins in various tumor types. Further, belinostat has been demonstrated to induce apoptosis and improve expression of the cyclin-dependent kinase inhibitor p21waf1 and p27, which are negative regulators of tumor growth [62].
Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mothana K. Al-Omari, Mai Elaarag, Raed M. Al-Zoubi, Ahmad R. Al-Qudimat, Ayman A. Zarour, Enas A. Al-Hurani, Zainab E. Fares, Leena M. Alkharraz, Mohanad Shkoor, Abdulilah D. Bani-Yaseen, Omar M. Aboumarzouk, Aksam Yassin, Abdulla A. Al-Ansari
Boronate belinostat 24 and boronate 5-fluorouracil 25 derivatives have been both shown to inhibit growth in mice breast cancer cell lines86,109. Boronate belinostat 24 prodrug in vivo was found to be more potent than belinostat alone, it inhibits and reduces the tumour volume in the MCF-7 xenograft tumour model. This prodrug targets MDA-MB-231 and MCF-7 breast cancer cell lines as well as A549 lung cancer cell line, and HeLa for cervical cancer cell line109. Some potential side effects of belinostat may include fatigue, nausea, vomiting, diarrhoea, loss of appetite, and hematological toxicities such as anaemia, thrombocytopenia, or neutropenia. In rare cases, severe hypersensitivity reactions or pulmonary toxicity may occur109.
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