6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Abstract

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 µmol/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.

Antiproliferative and Cytotoxic Activity of Xanthohumol and Its Non-Estrogenic Derivatives in Colon and Hepatocellular Carcinoma Cell Lines

“…This property prevents the formation of 8-PN, one of the most potent phytoestrogens known (Figure 1) [3,20,21]. Interestingly, 8-PN possesses anti-proliferative effects in vitro against the colon carcinoma cell line Caco-2, breast carcinoma line MCF-7, the melanoma line SK-MEL-28, and a Burkitt lymphoma cell line [21,22,23,24,25]. The estrogenic effects of 8-PN also show promising clinical results in treating postmenopausal symptoms, but these studies are usually short term and were not designed to assess the effect of potential cancer promoting properties [26].…”

Dietary Phytoestrogens and Their Metabolites as Epigenetic Modulators with Impact on Human Health

“…Indeed, 6-PN and a standardized hop extract selectively induced upregulation of AhR-dependent estrogen detoxification pathway by reducing of DNMT1-mediated inhibition of CYP1A1 transcription [ 228 ]. Moreover, Venturelli et al [ 229 ] have shown by in silico studies that both 6-PN and 8-PN can fit into catalytic site of HDAC 2, 4, 7 and 8 enzymes and interact with Zn ion for catalytic activities, so may be acting as pan-HDACs inhibitors. The in vitro experiments revealed that 6-PN and 8-PN can induce a rapid hyperacetylation of H3 histone within few hours after applying the PFs treatment on melanoma cells.…”

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

“…In addition, the effects of C15 urushiol and its triazole derivatives on the apoptosis of liver cancer cells have been qualitatively and quantitatively verified ( 132 ). Venturelli et al ( 133 ) reported that 6- and 8-prenylnaringenin enter into the 'foot pocket' of HDAC2 and combine with zinc ion of their catalytic center, subsequently inhibiting excessive proliferation of melanoma cells. N-[4-(Hydrazinecarbonyl)phenyl]-3,5,6-trimethylpyr- azine-2-carboxamide exhibits notable anticancer activity in vivo (IC 50 =1.60 μ M) ( 134 ) Among squaramide-based derivatives, the lead compound 42 exhibits good druggability by specifically inhibiting HDAC2 ( 67 ).…”