The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Zagni, Chiara; Floresta, Giuseppe; Monciino, Giulia; Rescifina, Antonio

doi:10.1002/med.21437

Cited by 110 publications

(83 citation statements)

References 198 publications

(315 reference statements)

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“…The therapeutic use of epigenetic inhibitors in treatment of cancers has been known for more than a decade, and several HDAC inhibitors like vorinostat and romidepsin have meanwhile been approved for anticancer therapy (e.g., reviewed in Schobert and Biersack, 2017; Zagni et al, 2017). Also, the antimalarial effects of inhibitors targeting HAT and HDAC enzymes have been explored in the past (e.g., Cui et al, 2007b; Andrews et al, 2008, 2009, 2012a; Chaal et al, 2010; Wheatley et al, 2010; Sumanadasa et al, 2012; Engel et al, 2015; Alves Avelar et al, 2017; Chua et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Profiling Defines Histone Acetylation as a Regulator of Gene Expression during Human-to-Mosquito Transmission of the Malaria Parasite Plasmodium falciparum

Ngwa

Kiesow

Papst

et al. 2017

Front. Cell. Infect. Microbiol.

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Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is mediated by the intraerythrocytic gametocytes, which, once taken up during a blood meal, become activated to initiate sexual reproduction. Because gametocytes are the only parasite stages able to establish an infection in the mosquito, they are crucial for spreading the tropical disease. During gametocyte maturation, different repertoires of genes are switched on and off in a well-coordinated sequence, pointing to regulatory mechanisms of gene expression. While epigenetic gene control has been studied during erythrocytic schizogony of P. falciparum, little is known about this process during human-to-mosquito transmission of the parasite. To unveil the potential role of histone acetylation during gene expression in gametocytes, we carried out a microarray-based transcriptome analysis on gametocytes treated with the histone deacetylase inhibitor trichostatin A (TSA). TSA-treatment impaired gametocyte maturation and lead to histone hyper-acetylation in these stages. Comparative transcriptomics identified 294 transcripts, which were more than 2-fold up-regulated during gametocytogenesis following TSA-treatment. In activated gametocytes, which were less sensitive to TSA, the transcript levels of 48 genes were increased. TSA-treatment further led to repression of ~145 genes in immature and mature gametocytes and 7 genes in activated gametocytes. Up-regulated genes are mainly associated with functions in invasion, cytoadherence, and protein export, while down-regulated genes could particularly be assigned to transcription and translation. Chromatin immunoprecipitation demonstrated a link between gene activation and histone acetylation for selected genes. Among the genes up-regulated in TSA-treated mature gametocytes was a gene encoding the ring finger (RING)-domain protein PfRNF1, a putative E3 ligase of the ubiquitin-mediated signaling pathway. Immunochemistry demonstrated PfRNF1 expression mainly in the sexual stages of P. falciparum with peak expression in stage II gametocytes, where the protein localized to the nucleus and cytoplasm. Pfrnf1 promoter and coding regions associated with acetylated histones, and TSA-treatment resulted in increased PfRNF1 levels. Our combined data point to an essential role of histone acetylation for gene regulation in gametocytes, which can be exploited for malaria transmission-blocking interventions.

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Section: Introductionmentioning

confidence: 99%

Transcriptional Profiling Defines Histone Acetylation as a Regulator of Gene Expression during Human-to-Mosquito Transmission of the Malaria Parasite Plasmodium falciparum

Ngwa

Kiesow

Papst

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Second, a potential way to overcome the highly immunosuppressive tumor microenvironment and low number of TILs is by inhibiting histone deacetylases (HDAC). Inhibition of HDACs lead to increased histone acetylation, resulting in increased gene expression [75]. Recently, both the HDAC inhibitor mocetinostat and inhibition of HDAC6 independently demonstrated a synergistic effect in combination with ICI, resulting in increased anti-tumor activity in NSCLC and ovarian cancer cell lines by increasing tumor antigen presentation and decreasing immune suppressive cell types [76,77].…”

Section: Discussionmentioning

confidence: 99%

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

Brahm

Linde

Enting

et al. 2020

Cancers

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The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.

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“…Epigenetic manipulation for chromatin remodeling can be recognized as a promising approach that results in the activation of silent gene clusters involved in the formation of polyketide, nonribosomal peptide, and hybrid natural products. Chemical approaches targeting histone and/or DNA of chromatin are well documented and have provided a rapid and global approach to mining the chemical diversity of microorganisms . Specifically, small‐molecule inhibitors of DNA methyl transferase (DMT) or histone deacetylase (HDAC) selectively or semiselectively influence secondary metabolism by binding to epigenome‐modifying enzyme targets .…”

Section: Novel Organisms and Manipulation Of Natural Metabolismmentioning

confidence: 99%

“…Chemical approaches targeting histone and/or DNA of chromatin are well documented and have provided a rapid and global approach to mining the chemical diversity of microorganisms. [153][154][155] Specifically, small-molecule inhibitors of DNA methyl transferase (DMT) or histone deacetylase (HDAC) selectively or semiselectively influence secondary metabolism by binding to epigenome-modifying enzyme targets. 153,156 A new, highly modified fatty acid amide, varitatin A (23) ( Fig.…”

Section: Chemical Epigenetic Manipulationmentioning

confidence: 99%

Strategies to diversify natural products for drug discovery

Lou

2017

Medicinal Research Reviews

222

130

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Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

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The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

Cited by 110 publications

References 198 publications

Transcriptional Profiling Defines Histone Acetylation as a Regulator of Gene Expression during Human-to-Mosquito Transmission of the Malaria Parasite Plasmodium falciparum

Transcriptional Profiling Defines Histone Acetylation as a Regulator of Gene Expression during Human-to-Mosquito Transmission of the Malaria Parasite Plasmodium falciparum

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

Strategies to diversify natural products for drug discovery

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