T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance

Piekarz, Richard; Robey, Robert W.; Zhan, Zhirong; Kayastha, Ganesh L.; Sayah, Anousheh; Abdeldaim, Amina H.; Torrico, Sonia; Bates, Susan E.

doi:10.1182/blood-2003-09-3068

Cited by 179 publications

(126 citation statements)

References 51 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…43 In contrast, the induction of apoptosis by different histone deacetylase inhibitors was dependent on the upregulation of p21. 44,45 With respect to 5-Aza-CdR-induced apoptosis in AML cells, further studies will be necessary to dissect the role of other p73 target genes, like PUMA and p53AIP. We found DNA methylation of p73 in AML cell lines and in primary AML blasts but not in normal PBMCs and epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Schmelz

Wagner

Dörken

et al. 2005

Intl Journal of Cancer

105

View full text Add to dashboard Cite

The DNA methylation inhibitor 5-Aza-2 -deoxycytidine (5-AzaCdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5-Aza-CdR induced apoptosis in AML cells (both p53 mutant and wild-type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome c and AIF and loss of mitochondrial membrane potential (⌬⌿m). Activation of caspase-3 (but not ؊6 and ؊8) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G 1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5-Aza-CdR-induced reexpression of the tumor-suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5-Aza-CdR. Therefore, 5-Aza-CdRmediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.Key words: 5-aza-2Ј-deoxycytidine; p21 WAF ; p73; p53; myeloid leukemia; DNA methylation DNA methylation is an epigenetic mechanism of gene regulation that plays a crucial role in carcinogenesis due to silencing of cancer-related genes. 1 Transcriptional blockage occurs as a consequence of methylated CpG islands in the 5Ј region of genes, which is mediated by DNMTs during DNA replication. 2 In contrast to gene mutation, DNA methylation is a reversible event open to attack by DNA methylation inhibitors like 5-Aza-CdR. As a nucleoside analogue, 5-Aza-CdR is integrated into DNA and inhibits DNA methylation by trapping DNMTs. While other methylation inhibitors like zebularine are known, most data are available for 5-Aza-CdR in terms of its clinical utility. Two phase II clinical studies have reported promising therapeutic activity of 5-Aza-CdR (decitabine) for patients with MDS 3 or CML. 4 Two other studies, enrolling mostly patients with AML, reported good response rates after decitabine treatment. 5,6 5-Aza-CdR effectively reverts methylation-dependent gene repression, as shown, e.g., for p15 INK4b in vitro and in vivo. 6 In AML cells, promoter hypermethylation has been reported for several other genes, including the estrogen receptor, E-cadherin 7 HIC1, calcitonin 8 and MYOD. 9 The molecular effects of 5-Aza-CdR can include histone deacetylation a...

show abstract

Section: Discussionmentioning

confidence: 99%

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Schmelz

Wagner

Dörken

et al. 2005

Intl Journal of Cancer

105

View full text Add to dashboard Cite

show abstract

“…The results have been especially good in patients with T-cell cutaneous lymphoma, and in some cases a long-term response has been observed 114,115 . The molecular basis for this response is being explored in vitro 116 . Tumour regression (in some cases quite dramatic) has also been observed in solid tumours 111,112 .…”

Section: Maximal Tolerated Dosementioning

confidence: 99%

“…Depsipeptide has been reported to be a substrate for P-glycoprotein (Pgp, also known as ATP-binding cassette subfamily B, member 1 (ABCB1)), and multidrug resistance-associated protein 1 (MRP1, also known as ABCC1), and to induce Pgp expression, indicating that resistance to HDACi might be drug-specific 116,118 .…”

Section: Maximal Tolerated Dosementioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

View full text Add to dashboard Cite

| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

show abstract

“…SAHA, LAQ824, LBH589A, and PXD-101 are hydroxamate HDAC inhibitors that have moved forward in clinical trials [Lindemann et al, 2004;Marks et al, 2004;Rosato and Grant, 2004;Piekarz et al, 2004b;Drummond et al, 2005;]. An oral preparation of SAHA is phase I and phase II clinical trials [Kelly et al, In Press].…”

Section: Clinical Trialsmentioning

confidence: 99%

Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

438

362

View full text Add to dashboard Cite

Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

show abstract

T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance

Cited by 179 publications

References 51 publications

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Prospects: Histone deacetylase inhibitors

Contact Info

Product

Resources

About

T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance

Cited by 179 publications

References 51 publications

5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Prospects: Histone deacetylase inhibitors

Contact Info

Product

Resources

About

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia