Vorinostat: A novel therapy for the treatment of cutaneous T-cell lymphoma

Kavanaugh, Shannon A.; White, Lisa A.; Kolesar, Jill

doi:10.2146/ajhp090247

Cited by 93 publications

(68 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…HDAC inhibitors are promising anti-cancer therapeutics that have demonstrated pre-clinical and clinical activities in haematological and solid cancers, and SAHA was the first of this class of compound to be FDA approved. [29][30][31][32][33] There have been several early phase clinical trials in advanced, chemotherapy-resistant CRC examining SAHA in combination with standard 5-Fluorouracil (5-FU)-based chemotherapy. [34][35][36] In one of these studies, 21/38 5-FU-refractory patients had stable disease and 1 had a partial response.…”

Section: Discussionmentioning

confidence: 99%

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

et al. 2012

View full text Add to dashboard Cite

FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'. Cell Death and Differentiation (2012) 19, 1317-1327 doi:10.1038/cdd.2012 published online 10 February 2012 FLIP is an anti-apoptotic protein that blocks the activation of apoptosis mediated by death receptors, such as Fas, TRAIL receptor 1 (TRAIL-R1/DR4) and TRAIL-R2 (DR5).1 By binding to the adaptor protein FADD, FLIP inhibits apoptosis by blocking the processing and activation of procaspase 8 (FLICE) by death receptor complexes termed DISCs (death-inducing signalling complexes). 2 We previously reported that FLIP inhibits apoptosis induced by chemotherapeutic agents 3 and that high FLIP expression is an independent adverse prognostic biomarker in colorectal cancer (CRC). 4 These and other studies have indicated that inhibition of FLIP constitutes a promising therapeutic strategy for the treatment of CRC. Ku70 and its binding partner Ku80 are critical components of the non-homologous end joining (NHEJ) DNA repair machinery.5 Ku70 is regulated by acetylation, which is mediated by the histone acetyl transferases (HATs); CREBbinding protein (CBP) and PCAF, and its acetylation can be enhanced by treating cells with histone deacetylase (HDAC) inhibitors.6 Ku70 acetylation disrupts its DNA-binding activity and sensitises cells to DNA-damaging agents. 7 In addition, cytoplasmic Ku70 binds to and regulates the pro-apoptotic Bcl-2 family member, Bax.6 Ku70 simultaneously inhibits Bax degradation via the ubiquitin proteasome system (UPS) and prevents its translocation to the mitochondria. 8 Moreover, it has been reported that Ku70 may have intrinsic deubiquitinating (DUB) activity.8 The Ku70-Bax complex is disrupted by Ku70 acetylation, which promotes Bax translocation to mitochondria and apoptosis induction. Herein, we report a novel interaction between FLIP and Ku70 that regulates FLIP stability. This interaction is acetylation-dependant and is disrupted by HDAC inhibitors with activity against HDAC6. Disruption of the Ku70-FLIP interaction subsequently leads to FLIP degradation by the UPS and induction of c...

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Two categories of drugs, affecting histone acetylation and DNA methylation, are currently considered in epigenetic therapy of cancer. In myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are already in clinical use (15,23). HDACi can open up chromatin by causing hyperacetylation of histones H3 and H4 (49).…”

mentioning

confidence: 99%

Genomic DNA Hypomethylation by Histone Deacetylase Inhibition Implicates DNMT1 Nuclear Dynamics

Arzenani

Zade

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Epigenetic modifications of chromatin play an important role in differentiation, aging, and tumorigenesis (41). Major epigenetic mechanisms include DNA methylation and covalent posttranslational modification of histone tails. These events switch chromatin between relatively "open" (expressed) and "closed" (suppressed) structures. Although there are several different histone modifications, the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs) are considered important regulators of chromatin structure (28). DNA methylation is an important epigenetic modification in the vertebrate genome which occurs mainly on cytosines located in CpG dinucleotide sequences (2). DNA methylation patterns are established by DNA methyltransferase 3a (DNMT3a) and DNMT3b, which are de novo DNA methyltransferases (DNMTs), and are mainly propagated by DNMT1, a maintenance methyltransferase (39). DNA methyltransferases are involved in the aberrant DNA methylation patterns frequently found in cancer cells (21). In addition, there is growing evidence that inappropriate gene expression by epigenetic events is crucial for the initiation and progression of cancer. These epigenetic abnormalities, including epigenetic silencing of tumor suppressor genes by abnormal promoter methylation, are likely to play an important role in tumor growth and metastasis when a substantial number of genes can be inactivated by DNA methylation in a tumor (20). In addition to DNA methylation, genome-wide changes in histone modifications are also found in cancer cells. Loss of acetylation at lysine 16 and trimethylation at lysine 20 of histone H4 have been reported as common hallmarks of human cancer (11).New insights into the high prevalence of epigenetic changes in cancer have led to novel therapeutic approaches in oncology that rely on the dynamic nature of epigenetic factors. The main idea behind these approaches is that abnormal epigenetic marks leading to gene silencing may be reversed. Two categories of drugs, affecting histone acetylation and DNA methylation, are currently considered in epigenetic therapy of cancer. In myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are already in clinical use (15,23). HDACi can open up chromatin by causing hyperacetylation of histones H3 and H4 (49). DNMTi, such as 5-aza-deoxycytidine, can induce genomic DNA hypomethylation (35). However, some gene promoters are not readily activated with either of the two inhibitors alone, but there are reports showing that HDACi and DNMTi can act synergistically to reactivate silenced genes (12,47). Therefore, the functional interaction between HDACs and DNMTs has been a key issue in epigenetic research. Trichostatin A (TSA), a general inhibitor for class I and II HDACs, has also been shown to reactivate methylation-silenced genes even in the absence of DNMT inhibitors (25). In addition, it has been reported that TSA decreases DNMT3b mRNA levels in endo...

show abstract

“…So thrombocytopenic effect of vorinostat may potentiate the anticoagulant effect of warfarin and may increase the chances of bleeding if these two drugs are used concomitantly. 15 Romidepsin: Romidepsin, a depsipeptide, was approved by the U.S. F.D.A. in 2009 for cutaneous T-cell lymphoma.…”

Section: Approved Hdacis Arementioning

confidence: 99%

Histone deacetylase inhibitors: pharmacotherapeutic implications as epigenetic modifier

Vishwakarma

Kumar

Sharma

et al. 2014

Int J Basic Clin Pharmacol

View full text Add to dashboard Cite

Vorinostat: A novel therapy for the treatment of cutaneous T-cell lymphoma

Abstract: Vorinostat, a novel HDAC inhibitor, is efficacious and well tolerated in patients with CTCL and is being investigated for its efficacy and safety in other types of cancers and as a part of combination therapy.

Cited by 93 publications

References 24 publications

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

Genomic DNA Hypomethylation by Histone Deacetylase Inhibition Implicates DNMT1 Nuclear Dynamics

Histone deacetylase inhibitors: pharmacotherapeutic implications as epigenetic modifier

Contact Info

Product

Resources

About