Romidepsin (FK228), A Histone Deacetylase Inhibitor and its Analogues in Cancer Chemotherapy

Pojani, Eftiola; Barlocco, Daniela

doi:10.2174/0929867327666200203113926

Cited by 31 publications

(21 citation statements)

References 97 publications

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“…While Romidepsin, also named Depsipeptide or FK228, is a potent inhibitor of HDAC1 and HDAC2, Entinostat (MS-275) mainly inhibits HDAC1 and HDAC3. Both compounds have been studied in vitro and also in clinical studies [ 29 , 30 , 31 ]. We further used RGFP966 to specifically target HDAC3 only [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells

Hoffmann

Meneceur

Hommel

et al. 2021

Genes

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Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted.

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Section: Introductionmentioning

confidence: 99%

Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells

Hoffmann

Meneceur

Hommel

et al. 2021

Genes

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“…The hypotheses rank from direct HIF-1/2 acetylation and degradation by pVHL to interactions with the HsP70/90 chaperone axis and decreased HIF-1/2 nuclear translocation [62]. Other promising and already approved HDAC inhibitors are romidepsin (FK228) [63], belinostat (PXD-101) [64], panobinostat (LBH-589) [65], and chidamide [66], for which effects on HIF have also been described by E. Pojani and D. Barlocco (Figure 2) [67].…”

Section: Inhibitors Of Hif-α Transcription Translation and Protein mentioning

confidence: 87%

Ways into Understanding HIF Inhibition

Schönberger

Fandrey

Prost-Fingerle

2021

Cancers

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Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

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“…HDAC isoenzymes were reported to be high in malignant cells [ 109 ]. HDAC inhibitors can reactivate the expression of tumor suppressors and have emerged as one type of well-characterized epigenome-targeting agents that are capable of suppressing both histone acetylation and non-histone acetylation to resolve tumors [ 110 ], halt cancer metastasis [ 111 ], reprogram cancer cell metabolism [ 112 , 113 ], modulate the immune [ 114 ], chemo [ 115 ] and radio [ 116 ] sensitivity of cancer cells. Several HDAC inhibitors have been developed and approved by the Food and Drug Administration (FDA) for cancer treatment that represent distinct HDAC specificity.…”

Section: Combining Hdac Inhibitors With Cold Atmospheric Plasma Provides Novel Onco-therapeutic Opportunitiesmentioning

confidence: 99%

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Thompson

et al. 2022

Cancers

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Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects.

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Romidepsin (FK228), A Histone Deacetylase Inhibitor and its Analogues in Cancer Chemotherapy

Cited by 31 publications

References 97 publications

Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells

Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells

Ways into Understanding HIF Inhibition

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

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