Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 51, Issue 2, Pages 543-556Publisher
KARGER
DOI: 10.1159/000495275
Keywords
6-prenylnaringenin; 8-prenylnaringenin; 6-PN; 8-PN; HDAC; Histone deacetalyse inhibition; Melanoma; Therapy; Hops
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Funding
- University Hospital Tuebingen [1966-0-0]
- European Foundation for Alcohol Research (ERAB) [EA 15 28]
- Else-Uebelmesser-Stiftung of the University of Tuebingen
- Institutional Strategy of the Eberhard Karls University of Tuebingen (Deutsche Forschungsgemeinschaft [DFG]) [ZUK 639]
- Wissenschaftsfoerderung der Deutschen Brauwirtschaft e.V. [B103]
- Open Access Publishing Fund of the Eberhard Karls University of Tuebingen
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Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results:In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 mu mol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.
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