Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

Pinkerneil, Maria; Hoffmann, Michèle J.; Kohlhof, Hella; Schulz, Wolfgang A.; Niegisch, Günter

doi:10.1007/s11523-016-0444-7

Cited by 53 publications

(73 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4SC‐202 is a novel small‐molecule inhibitor selectively targeting class I HDACs 1/2/3 and the lysine‐specific demethylase LSD1 . Notably, 4SC‐202 has shown excellent safety and promising anti‐leukemic activity in a recent phase I clinical trial (see TOPAS study at http://clinicaltrials.gov trial no.…”

Section: Resultsmentioning

confidence: 99%

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC‐202 blocks oncogenic hedgehog‐GLI signaling and overcomes smoothened inhibitor resistance

Gruber

Peer

Elmer

et al. 2017

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO. In this study, we report that 4SC‐202, a novel clinically validated inhibitor of class I histone deacetylases (HDACs), efficiently blocks HH/GLI signaling. Notably, 4SC‐202 treatment abrogates GLI activation and HH target gene expression in both SMOi‐sensitive and ‐resistant cells. Mechanistically, we propose that the inhibition of HDACs 1/2/3 is crucial for targeting oncogenic HH/GLI signaling, and that class I HDAC inhibitors either in combination with SMOi or as second‐line therapy may improve the treatment options for HH‐associated malignancies with SMOi resistance.

show abstract

Section: Resultsmentioning

confidence: 99%

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC‐202 blocks oncogenic hedgehog‐GLI signaling and overcomes smoothened inhibitor resistance

Gruber

Peer

Elmer

et al. 2017

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…This broad specificity makes it difficult to interpret the results of inhibitor treatment in terms of precise biochemical mechanisms. Attempts have been made, with some success, to synthesize derivatives specific for individual HDACs and one such (a benzamide, 4SC‐202) is in a phase I clinical trial (Table ). However, the functional redundancy of HDACs, particularly class I enzymes , may reduce the clinical effectiveness of enzyme‐specific inhibitors.…”

Section: Hdaci Generally Inhibit Several Members Of the Hdac Familymentioning

confidence: 99%

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Halsall

Turner

2016

BioEssays

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers.Also see the video abstract here.

show abstract

“…The drug 4SC-202 has been shown to inhibit the growth of colorectal cancer cells, 38 hepatocellular carcinoma cells, 39 and urothelial carcinoma cells. 40 Here, it was demonstrated that 4SC-202 also blocks the growth of medulloblastoma cell lines, a cancer type with involvement of REST/ NRSF. 20,23 In conclusion, our system provides a toolbox for the expression of the central transcriptional repressor complex, CRC, allowing the complex to be assembled in a stepwise manner.…”

Section: Discussionmentioning

confidence: 89%

“…Accordingly, it was demonstrated that the drug efficiently inhibited both HDAC1 and LSD1 in the CRC isolates. The drug 4SC‐202 has been shown to inhibit the growth of colorectal cancer cells, hepatocellular carcinoma cells, and urothelial carcinoma cells . Here, it was demonstrated that 4SC‐202 also blocks the growth of medulloblastoma cell lines, a cancer type with involvement of REST/NRSF …”

Section: Discussionmentioning

confidence: 90%

Stepwise assembly of functional C‐terminal REST/NRSF transcriptional repressor complexes as a drug target

et al. 2017

View full text Add to dashboard Cite

In human cells, thousands of predominantly neuronal genes are regulated by the repressor element 1 (RE1)-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF). REST/NRSF represses transcription of these genes in stem cells and non-neuronal cells by tethering corepressor complexes. Aberrant REST/NRSF expression and intracellular localization are associated with cancer and neurodegeneration in humans. To date, detailed molecular analyses of REST/NRSF and its C-terminal repressor complex have been hampered largely by the lack of sufficient amounts of purified REST/NRSF and its complexes. Therefore, the aim of this study was to express and purify human REST/NRSF and its C-terminal interactors in a baculovirus multiprotein expression system as individual proteins and coexpressed complexes. All proteins were enriched in the nucleus, and REST/NRSF was isolated as a slower migrating form, characteristic of nuclear REST/NRSF in mammalian cells. Both REST/NRSF alone and its C-terminal repressor complex were functionally active in histone deacetylation and histone demethylation and bound to RE1/neuron-restrictive silencer element (NRSE) sites. Additionally, the mechanisms of inhibition of the small-molecule drugs 4SC-202 and SP2509 were analyzed. These drugs interfered with the viability of medulloblastoma cells, where REST/NRSF has been implicated in cancer pathogenesis. Thus, a resource for molecular REST/NRSF studies and drug development has been established.

show abstract

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

Cited by 53 publications

References 53 publications

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC‐202 blocks oncogenic hedgehog‐GLI signaling and overcomes smoothened inhibitor resistance

Targeting class I histone deacetylases by the novel small molecule inhibitor 4SC‐202 blocks oncogenic hedgehog‐GLI signaling and overcomes smoothened inhibitor resistance

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Stepwise assembly of functional C‐terminal REST/NRSF transcriptional repressor complexes as a drug target

Contact Info

Product

Resources

About