Abstract
The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate.
Highlights
Histone deacetylases (HDACs) are epigenetic regulators of chromatincondensation and, play an important role in various crucial cellular processes [1]
HDACs are overexpressed in various cancers and exert a strong impact on cancer cell proliferation, dissemination and metastasis [2]
Some HDAC inhibitors such as vorinostat/SAHA and panobinostat are already approved for the treatment of hematologic cancer and are currently under intensive investigation for their suitability in solid tumors [3]
Summary
Histone deacetylases (HDACs) are epigenetic regulators of chromatin (de-)condensation and, play an important role in various crucial cellular processes [1]. HDACs are overexpressed in various cancers and exert a strong impact on cancer cell proliferation, dissemination and metastasis [2]. HDAC inhibitors are a promising class of compounds for targeted cancer therapy. Some HDAC inhibitors such as vorinostat/SAHA (suberoylanilide hydroxamic acid) and panobinostat are already approved for the treatment of hematologic cancer and are currently under intensive investigation for their suitability in solid tumors [3]. Severe drawbacks have emerged during the clinical application of single HDAC inhibitors such as intrinsic or acquired drug resistance. The search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer
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