scholarly journals Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a Rabbit Retinoblastoma Model

2021 ◽  
Vol 62 (14) ◽  
pp. 8
Author(s):  
Jessica V. Kaczmarek ◽  
Carley M. Bogan ◽  
Janene M. Pierce ◽  
Yuankai K. Tao ◽  
Sheau-Chiann Chen ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Retinal Toxicity ◽  
Vitreous Seeds

scholarly journals Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study

2021 ◽  
pp. bjophthalmol-2020-318529
Author(s):  
Carley M Bogan ◽  
Jessica V Kaczmarek ◽  
Janene M Pierce ◽  
Sheau-chiann Chen ◽  
Kelli L Boyd ◽  
...  
Keyword(s):  
Cohort Study ◽  
Clinical Study ◽  
Tumour Cell ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Rabbit Model ◽  
Retinal Toxicity ◽  
Apoptosis Induction ◽  
Dose Levels ◽  
Vitreous Seeds

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

scholarly journals Resistance after Chronic Application of the HDAC-Inhibitor Valproic Acid Is Associated with Elevated Akt Activation in Renal Cell Carcinoma In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53100 ◽  
Author(s):  
Eva Juengel ◽  
Jasmina Makarević ◽  
Igor Tsaur ◽  
Georg Bartsch ◽  
Karen Nelson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Valproic Acid ◽  
Cell Carcinoma ◽  
Hdac Inhibitor ◽  
Renal Cell ◽  
Akt Activation

Acute Aminoglycoside Retinal Toxicity In Vivo and In Vitro

2005 ◽  
Vol 46 (12) ◽  
pp. 4804 ◽  
Author(s):  
Heather A. Hancock ◽  
Clyde Guidry ◽  
Russell W. Read ◽  
Edgar L. Ready ◽  
Timothy W. Kraft
Keyword(s):  
Retinal Toxicity

scholarly journals Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability

2019 ◽  
Vol 12 (4) ◽  
pp. 180 ◽  
Author(s):  
Changde Zhang ◽  
Shanchun Guo ◽  
Qiu Zhong ◽  
Qiang Zhang ◽  
Ahamed Hossain ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Hdac Inhibitor ◽  
Active Drug ◽  
Hydrolysis Product ◽  
Liver Microsomes ◽  
Tumor Model ◽  
Maximum Plasma ◽  
Metabolic Products

ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)2-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t1/2) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (Cmax) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)2-452 showed an AUC of 8306 ng/mL*h and Cmax of 931 ng/mL 3 h after drug administration.

scholarly journals Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Jane L. Roberts ◽  
Laurence Booth ◽  
Andrew Poklepovic ◽  
Paul Dent
Keyword(s):  
Hdac Inhibitor ◽  
Kinase Inhibitor ◽  
Hdac Inhibitors ◽  
Autophagic Flux ◽  
Drug Induced ◽  
Ampk Signaling ◽  
Knock Down ◽  
Reduce Tumor Growth ◽  
Sarcoma Cells

We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Raptor S722/S792 phosphorylation. Individually, all drugs increased phosphorylation of ATM S1981, AMPKα T172, ULK1 S317 and ATG13 S318 and reduced ULK1 S757 phosphorylation; this correlated with enhanced autophagic flux. Increased phosphorylation of ULK1 S317 and of Raptor S722/S792 required ATM-AMPK signaling. ULK1 S757 is a recognized site for mTORC1 and knock down of either ATM or AMPKα reduced the drug-induced dephosphorylation of this site. Combined exposure of cells to axitinib and an HDAC inhibitor significantly reduced the expression of HDAC1, HDAC2, HDAC3, HDAC4, HDAC6 and HDAC7. No response was observed for HDACs 10 and 11. Knock down of ULK1, Beclin1 or ATG5 prevented the decline in HDAC expression, as did expression of a constitutively active mTOR protein. Axitinib combined with HDAC inhibitors enhanced expression of Class I MHCA and reduced expression of PD-L1 which was recapitulated via knock down studies, particularly of HDACs 1 and 3. In vivo, axitinib and the HDAC inhibitor entinostat interacted to significantly reduce tumor growth. Collectively our findings support the exploration of axitinib and HDAC inhibitors being developed as a novel sarcoma therapy.

scholarly journals Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo

2014 ◽  
Vol 20 (5) ◽  
pp. 1274-1287 ◽  
Author(s):  
Chun-Han Chen ◽  
Mei-Chuan Chen ◽  
Jing-Chi Wang ◽  
An-Chi Tsai ◽  
Ching-Shih Chen ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cells ◽  
Hdac Inhibitor ◽  
Synergistic Interaction ◽  
Liver Cancer Cells

scholarly journals The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo

Oncotarget ◽  
2017 ◽  
Vol 8 (23) ◽  
pp. 37409-37422 ◽  
Author(s):  
Annarita Scialdone ◽  
Muhammad Sharif Hasni ◽  
Jesper Kofoed Damm ◽  
Andreas Lennartsson ◽  
Urban Gullberg ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Hdac Inhibitor ◽  
Cd20 Expression

scholarly journals Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Ying Yang ◽  
Nandan Wu ◽  
Yihui Wu ◽  
Haoting Chen ◽  
Jin Qiu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Apoptosis ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Chemotherapeutic Drug ◽  
Sprague Dawley ◽  
Fundus Fluorescein Angiography ◽  
Intravitreal Chemotherapy ◽  
Vitreous Seeds

Abstract Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds.

scholarly journals Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

2012 ◽  
Vol 56 (7) ◽  
pp. 3849-3856 ◽  
Author(s):  
Subathdrage D. M. Sumanadasa ◽  
Christopher D. Goodman ◽  
Andrew J. Lucke ◽  
Tina Skinner-Adams ◽  
Ishani Sahama ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
Parasite Life Cycle ◽  
Nonhistone Proteins ◽  
Content Type

ABSTRACTHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, thein vitroandin vivoantiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth ofPlasmodium falciparumasexual-stage parasitesin vitro(50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited thein vitrogrowth of exoerythrocytic-stagePlasmodiumparasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimentalin vivomurine model of cerebral malaria, orally administered SB939 significantly inhibitedP. bergheiANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor

2017 ◽  
Vol 400 ◽  
pp. 47-60 ◽  
Author(s):  
Yun Wang ◽  
Maoxing Liu ◽  
Yanli Jin ◽  
Sheng Jiang ◽  
Jingxuan Pan
Keyword(s):  
Uveal Melanoma ◽  
Hdac Inhibitor
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