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

scholarly journals Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

2013 ◽  
Vol 4 (9) ◽  
pp. 858-862 ◽  
Author(s):  
Qingqing Meng ◽  
Feng Li ◽  
Sheng Jiang ◽  
Zheng Li
Keyword(s):  
Pet Imaging ◽  
Histone Deacetylases

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.

Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl–positive human acute leukemia cells

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3236-3239 ◽  
Author(s):  
Ramadevi Nimmanapalli ◽  
Lianne Fuino ◽  
Corinne Stobaugh ◽  
Victoria Richon ◽  
Kapil Bhalla
Keyword(s):  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Blast Crisis ◽  
Cell Types ◽  
Suberoylanilide Hydroxamic Acid ◽  
Cytotoxic Effects ◽  
Protein Levels ◽  
Myelocytic Leukemia ◽  
Deacetylase Inhibitor ◽  
Induced Apoptosis

Abstract Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl–expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P < .05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-xL. Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34+ leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.

scholarly journals In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Nobuyoshi Fukumitsu ◽  
Skye Hsin-Hsien Yeh ◽  
Leo Garcia Flores II ◽  
Uday Mukhopadhyay ◽  
Daniel Young ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Histone Deacetylases ◽  
Histone Deacetylation ◽  
Antitumor Effects ◽  
Neuroprotective Effects ◽  
Positron Emission ◽  
Group A ◽  
Expression Activity ◽  
Group B

Background. Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results. The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment.

scholarly journals Design and Synthesis of Small Molecules Based on a Substructural Analysis of the Histone Deacetylase Inhibitors TSA and SAHA

2011 ◽  
Vol 8 (3) ◽  
pp. 1394-1400
Author(s):  
Lynda Ekou ◽  
Tchirioua Ekou ◽  
Javier Garcia ◽  
Isabelle Opalinski ◽  
Jean Pierre Gesson
Keyword(s):  
Small Molecules ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Suberoylanilide Hydroxamic Acid ◽  
Considerable Potential ◽  
Design And Synthesis

Inhibitors of histone deacetylases (HDACs) are patent inducers of differentiation and bear considerable potential as drugs for chemoprevention and treatment of cancer. In this paper, we have investigated three synthetic, inhibitors A1a,b, A2a. Analogue hybrid trichostatine A (TSA), suberoylanilide hydroxamic acid SAHA, in order to seek new histone deacetylases (HDACs) inhibitors.

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