Concept: Hydroxamic acids
Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders.
To improve the bioavailability and anticancer potential of suberoylanilide hydroxamic acid (SAHA) by developing a drug-loaded polymeric nanomicellar system.
Single-agent post-autologous transplant maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma. The tolerability and effectiveness of combination post-transplant maintenance therapy is unknown, so we investigated lenalidomide and vorinostat (suberoylanilide hydroxamic acid) in this setting, hypothesizing that the regimen would be well tolerated and associated with an improved post-transplant response. This trial followed a standard 3 × 3 dose escalation phase 1 design. Vorinostat was administered beginning day +90 post-haematopoietic stem cell transplantation for days 1-7 and 15-21, and lenalidomide was started at 10 mg days 1-21, both on a 28-d cycle. The primary endpoint was maximum tolerated dose and dose limiting toxicities were assessed during the first cycle. Treatment was well tolerated in 16 enrolled patients. During Cycle 1, the most common toxicities included cytopenias, gastrointestinal complaints and fatigue. Seven patients improved their transplant response after starting combination therapy. The median follow-up was 38·4 months, and the median progression-free survival and overall survival have yet to be reached. This oral post-transplant maintenance regimen was well tolerated. This is the first trial to publish results on the use of a histone deacetylase inhibitor in the maintenance setting, and it provides rationale for the ongoing randomized trial in maintenance (ISRCTN 49407852).
Cultivation of the marine-derived Aspergillus versicolor MCCC 3A00080 with the addition of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), significantly enhanced the diversity of secondary metabolites. From the culture treated, a new biphenyl derivative, named versiperol A (1), along with two known compounds, 2,4-dimethoxyphenol (2) and diorcinol (3) were isolated. The structures of 1-3 were established based on spectroscopic analysis and comparison with literature data. Among the isolates, versiperol A (1) exhibited modest inhibition of Staphylococcus aureus growth with MIC value of 8 μg/mL.
Hydroxamic acids (RC(O)NHOH) form a class of compounds, which display interesting chemical and biological properties The chemistry of RC(O)NHOH) is associated with one- and two-electron oxidations forming the respective nitroxide radical (RC(O)NHO•) and acyl nitroso (RC(O)N=O), respectively, which are relatively unstable species. In the present study the kinetics and mechanism of •NO2 reaction with nitroxide radicals derived from acetohydroxamic acid, suberohydroxamic acid, benzohydroxamic acid and suberoylanilide hydroxamic acid have been studied in alkaline solutions. Ionizing radiation was used to generate about equal yields of these radicals demonstrating that the oxidation of the transient nitroxide radical by •NO2 produces HNO and nitrite at about equal yields. The rate constant of •NO2 reaction with the nitroxide radical derived from acetohydroxamic acid has been determined to be (2.5 ± 0.5) x 109 M-1s-1. This reaction forms a transient intermediate absorbing at 314 nm, which decays via a first-order reaction whose rate increases upon increasing the pH or the hydroxamic acid concentration. Transient intermediates absorbing around 314 nm are also formed during the oxidation of hydroxamic acids by H2O2 catalyzed by horseradish peroxidase. It is shown that HNO is formed during the decomposition of these intermediates, and therefore they are assigned to acyl nitroso compounds. This study provides for the first time a direct spectrophotometric detection of acyl nitroso compounds in aqueous solutions allowing the study of their chemistry and reaction kinetics.
New tuberculosis (TB) drug treatment regimens are urgently needed. We evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line TB drugs against intracellular Mycobacterium tuberculosis (M. tb).
Efficacy and Safety Comparison Between Suberoylanilide Hydroxamic Acid and Mitomycin C in Reducing the Risk of Corneal Haze After PRK Treatment In Vivo
- Journal of refractive surgery (Thorofare, N.J. : 1995)
- Published 10 months ago
This study compared the efficacy and safety of suberoylanilide hydroxamic acid (SAHA) and mitomycin C (MMC) up to 4 months in the prevention of corneal haze induced by photorefractive keratectomy (PRK) in rabbits in vivo.
Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has preclinical efficacy in hepatocellular carcinoma (HCC), despite an unclear molecular mechanism. We sought to further investigate the effects of SAHA on HCC. We hypothesize SAHA will inhibit HCC cellular proliferation through apoptosis and aid in further profiling SAHA’s effect on HCC oncogenic pathways.
With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I-L, 1-4). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC50 values ranging from 0.84 to 1.35μM.
Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy
- Cancer research and treatment : official journal of Korean Cancer Association
- Published about 2 years ago
When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid; SAHA) when administered as a potential radiosensitiser.