scholarly journals Cardiomyogenic Differentiation of Human Dental Follicle-derived Stem Cells by Suberoylanilide Hydroxamic Acid and Their In Vivo Homing Property

2016 ◽  
Vol 13 (11) ◽  
pp. 841-852 ◽  
Author(s):  
Iel-Yong Sung ◽  
Han-Na Son ◽  
Imran Ullah ◽  
Dinesh Bharti ◽  
Ju-Mi Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
Dental Follicle ◽  
Cardiomyogenic Differentiation

Synergistic Preclinical Activity of Bortezomib with Suberoylanilide Hydroxamic Acid (SAHA) in Primary Effusion Lymphoma (PEL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1650-1650
Author(s):  
Shruti Bhatt ◽  
Brittany Ashlock ◽  
Ngoc Toomey ◽  
Enrique Mesri ◽  
Juan Carlos Ramos ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Primary Effusion Lymphoma ◽  
Suberoylanilide Hydroxamic Acid ◽  
Lytic Gene ◽  
Lytic Reactivation ◽  
Apoptotic Genes

Abstract Abstract 1650 Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma typically presenting as effusions in the serous body cavities without a contiguous tumor mass. PEL may develop in elderly immunosuppressed HIV-negative individuals but more commonly affects HIV-positive patients, accounting for 4% of all lymphomas in this population. Kaposi's sarcoma-associated herpesvirus (KSHV) is directly implicated in the pathogenesis of PEL, however in most patients the malignant B cells are also coinfected with Epstein-Barr virus which may facilitate transformation. Current chemotherapeutic approaches result in dismal outcome of PEL patients with a median survival of only 6 months. Consequently, development of new therapeutic approaches is urgently needed. Recently we reported development of the UM-PEL1 direct xenograft mice model reproducing human PEL (Sarosiek, PNAS 2010) in which bortezomib (BORT) induced virus lytic reactivation leading to malignant B cell death and transient remission of the PEL in vivo. Further improvement on this monotherapy is warranted. Recent studies have shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor is a highly effective viral lytic-cycle inducer. As herpesviruses are dependent on the proteasome for replication and mature viral production, induction of lytic replication with concomitant inhibition of the proteasome may provide a highly targeted strategy for eradicating KSHV infected cells without leading to increased viremia. Consequently, we hypothesized that combining BORT with SAHA may act synergistically in PEL tumors. Incubation of human PEL cell lines, UM-PEL1, BC1, BC3 and BC5 with BORT-SAHA resulted in increased apoptotis compared to individual treatment with BORT or SAHA, as assayed by flow cytometry using YO-PRO/PI staining. Concordantly, a statistically significant decrease in UM-PEL1 cell proliferation and viability, as examined by an MTT assay, was observed at 48 and 72 hours following combination therapy as compared to untreated cells or cells treated individually with BORT or SAHA. Cell cycle analysis demonstrated that BORT-SAHA combination induced more pronounced G1 cell cycle arrest and apoptosis as compared to individual treatments. SAHA induced a more robust KSHV lytic reactivation compared to BORT. Intriguingly, the BORT-SAHA combination led to an increased expression of the master lytic transactivator RTA and thymidine kinase, however the late lytic gene, K8.1, showed reduced mRNA expression relative to the individual SAHA treatment. These findings were further confirmed by immunofluorescence staining of the K8.1 protein suggesting that BORT could inhibit mature virion production in lytically reactivated malignant B-cells. To comprehensively examine the activity of the BORT-SAHA combination compared to individual BORT or SAHA treatments in vivo, we used UM-PEL1 direct xenograft model. Mice receiving intraperitoneal BORT-SAHA combination showed statistically significant prolonged survival compared to all the control treatments (p<0.001). Since PEL cells are known to be highly dependent on NF-κB for survival, we examined whether the apoptosis induced by the combination treatment was due to the inhibition of this pro-survival pathway. In contrast to our previous observations that individual BORT treatment did not alter NF-κB activity, the in vivo addition of SAHA led to NF-κB inhibition as demonstrated by gel shift assay. Moreover, Western blotting demonstrated downregulation of anti-apoptotic genes, upregulation of pro-apoptotic genes along with the rise in the p53, p21 and increased acetylation of histone 3 in the combination treated mice versus BORT alone. Further, RTA and early lytic gene expression confirmed our in vitro findings that KSHV lytic reactivation is enhanced in the BORT-SAHA treated mice compared to individual treatments. However, transcription of all late lytic genes tested (gB, K8.1, gM, ORF38, ORF67, ORF68) was uniformly inhibited in the animals treated with the BORT-SAHA as compared to SAHA alone, suggesting that the virus was unable to complete the full replicative cycle. In conclusion, this study demonstrates strong pre-clinical activity of the combination of proteasome inhibitor with HDAC inhibitor as a potent anti-PEL therapy that triggers apoptosis by prompting KSHV lytic reactivation without increasing infectious virus production. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Improves Energetic Status and Cardiomyogenic Differentiation of Human Dilated Myocardium-Derived Primary Mesenchymal Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 4845
Author(s):  
Rokas Miksiunas ◽  
Kestutis Rucinskas ◽  
Vilius Janusauskas ◽  
Siegfried Labeit ◽  
Daiva Bironaite
Keyword(s):  
Membrane Potential ◽  
Histone Deacetylase ◽  
Mitochondrial Membrane Potential ◽  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Mitochondrial Membrane ◽  
Troponin T ◽  
Suberoylanilide Hydroxamic Acid ◽  
Hdac Activity ◽  
Cardiomyogenic Differentiation

Background. In this study the effect of histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on the energetic status and cardiomyogenic differentiation of human healthy and dilated myocardium-derived mesenchymal stromal cells (hmMSC) have been investigated. Methods. The hmMSC were isolated from the healthy and dilated post-operation heart biopsies by explant outgrowth method. Cell proliferation, HDAC activity, mitochondrial membrane potential, and level of adenosine triphosphate (ATP) were evaluated. The effect of SAHA on mitochondrial parameters has been investigated also by Seahorse XF analyzer and cardiomyogenic differentiation was confirmed by the expression of transcription factor NK2 Homeobox 5 (Nkx2.5), cardiac troponin T and alpha cardiac actin at gene and protein levels. Results. Dilated myocardium-derived hmMSC had almost 1.5 folds higher HDAC activity compared to the healthy cells and significantly lower mitochondrial membrane potential and ATP level. HDAC class I and II inhibitor SAHA improved energetic status of mitochondria in dilated myocardium-isolated hmMSC and increased expression of cardiac specific proteins during 14 days of exposure of cells to SAHA. Conclusions. HDAC inhibitor SAHA can be a promising therapeutic for dilated cardiomyopathy (DCM). Dilated hmMSC exposed to SAHA improved energetic status and, subsequently, cardiomyogenic differentiation. Data suggest that human dilated myocardium-derived MSC still have cardio tissue regenerative potential, which might be stimulated by HDAC inhibitors.

In Vitro and In Vivo Cardiomyogenic Differentiation of Amniotic Fluid Stem Cells

2010 ◽  
Vol 7 (2) ◽  
pp. 364-380 ◽  
Author(s):  
Sveva Bollini ◽  
Michela Pozzobon ◽  
Muriel Nobles ◽  
Johannes Riegler ◽  
Xuebin Dong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amniotic Fluid ◽  
Amniotic Fluid Stem Cells ◽  
Cardiomyogenic Differentiation

scholarly journals Enhanced osteogenic differentiation of human periodontal ligament stem cells by suberoylanilide hydroxamic acid

BIOCELL ◽  
2020 ◽  
Vol 44 (3) ◽  
pp. 389-400
Author(s):  
YUNZE XUAN ◽  
BIN JIN ◽  
SAYAN DEB DUTTA ◽  
MENGMENG LIU ◽  
ZAIXIAN SHEN ◽  
...  
Keyword(s):  
Stem Cells ◽  
Osteogenic Differentiation ◽  
Periodontal Ligament ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
Periodontal Ligament Stem Cells

scholarly journals Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

2014 ◽  
Vol 58 (11) ◽  
pp. 6790-6806 ◽  
Author(s):  
Gregory Q. Del Prete ◽  
Rebecca Shoemaker ◽  
Kelli Oswald ◽  
Abigail Lara ◽  
Charles M. Trubey ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Nonhuman Primate ◽  
Hydroxamic Acid ◽  
Rhesus Macaques ◽  
Viral Rna ◽  
Repeat Dose ◽  
Suberoylanilide Hydroxamic Acid ◽  
Combination Antiretroviral Therapy ◽  
The Impact

ABSTRACTNonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool.Ex vivoSAHA treatment of CD4+T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration.In vivovirologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression forin vivoassessments of AIDS virus functional cure/eradication approaches.

scholarly journals Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo

2005 ◽  
Vol 93 (4) ◽  
pp. 992-999 ◽  
Author(s):  
Ilker Y. Eyupoglu ◽  
Eric Hahnen ◽  
Rolf Buslei ◽  
Florian A. Siebzehnrubl ◽  
Nicolai E. Savaskan ◽  
...  
Keyword(s):  
Hydroxamic Acid ◽  
Ex Vivo ◽  
Suberoylanilide Hydroxamic Acid

scholarly journals In Vivo PET Imaging of Histone Deacetylases by18F-Suberoylanilide Hydroxamic Acid (18F-SAHA)

2011 ◽  
Vol 54 (15) ◽  
pp. 5576-5582 ◽  
Author(s):  
J. Adam Hendricks ◽  
Edmund J. Keliher ◽  
Brett Marinelli ◽  
Thomas Reiner ◽  
Ralph Weissleder ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid
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