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Hypoxia, a typical feature of locally advanced solid tumors including prostate cancer, is a critical contributor to tumor progression and causes resistance to therapy. In this study, we investigated the effects of chrysin on tumor progression in hypoxic PC-3 cells. Chrysin exerted a significant inhibitory effect on 3D cell growth under normoxic and hypoxic conditions. It also decreased the hypoxia-induced vasculogenic mimicry and attenuated the expression of HIF-1α and VE-cadherin. Chrysin inhibited HIF-1α accumulation in a concentration- and time-dependent manner in hypoxic PC-3 cells, while also suppressing the expression of HIF-1α by inhibiting SPHK-1 in both CoCl2 and hypoxic PC-3 cells. At high concentrations of chrysin, there was a greater increase in apoptosis in the hypoxic cells compared to that in normoxic cells, which was accompanied by sub-G1 phase arrest. Chrysin-induced apoptosis inhibited VEGF and Bcl-2 and induced the cleavage of PARP and caspase-3. SPHK-1 knockdown induced apoptosis and inhibited epithelial–mesenchymal transition. Consistent with the in vitro data, 50 mg/kg of chrysin suppressed the tumor growth of PC-3 xenografts by 80.4% compared to that in the untreated control group. The immunohistochemistry of tumor tissues revealed decreased Ki-67, HIF-1α, and VEGF expression in the chrysin-treated group compared to an untreated control. Western blotting data for tumor tissues showed that chrysin treatment decreased SPHK-1, HIF-1α, and PARP expression while inducing caspase-3 cleavage. Overall, our findings suggest that chrysin exerts anti-tumor activity by inhibiting SPHK-1/HIF-1α signaling and thus represents a potent chemotherapeutic agent for hypoxia, which promotes cancer progression and is related to poor prognoses in prostate cancer patients.

Abstract Background Rhus verniciflua Stokes is an Asian tree species that is used as a food supplement and traditional medicine in Korea. However, its use is restricted by its potential to cause allergy. Thus, allergen-free R. verniciflua extracts are currently being marketed as a functional health food in Korea. In the present study, three different allergen-free R. verniciflua extracts (DRVE, FRVE, and FFRVE) were produced by detoxification of R. verniciflua, and their properties and constituents were compared. Methods The main components and properties (antibacterial, antioxidant, anticancer, and hepatic lipogenesis inhibitory effects) of the three allergen-free extracts were compared. Moreover, the major phenolic constituents of R. verniciflua, including gallic acid, fustin, fisetin, and quercetin, were analyzed in the three extracts. Results DRVE was superior to the two other extracts with regard to antioxidant activity, while FRVE was superior with regard to antimicrobial activity and suppression of hepatic lipogenesis. FRVE exhibited lipid-lowering effects by lowering sterol regulatory element-binding protein 1 and triglyceride levels, and promoting the activation of peroxisome proliferator-activated receptor and AMP-activated protein kinase in an in vitro model of non-alcoholic fatty liver. Conclusions Overall, our findings demonstrate various differences among the three extracts. This suggests that functional and bioactive compounds present in R. verniciflua could be altered by the detoxification process, and this property could be considered in the development of functional health foods in the future.

Heamatang (HMT) is a classic medicinal formula used in traditional Chinese and Korean medicine; it contains seven distinct components, mainly of herbal origin. HMT is used as an antiaging remedy, treating urinary disorders and increasing energy and vitality. However, the therapeutic applications of this formula have not been evaluated with evidence-based science. Therefore, we assessed HMT through various in vitro methods, including cell viability assay, fluorescence-activated cell sorting assay (FACS), Western blotting, migration assay, three-dimensional (3D) cell culture, siRNA-mediated PAK-1 knockdown, and crystal violet assays. HMT decreased PAK-1 expression in PC-3 cells and inhibited cell viability, growth, and motility. The inhibition of cell motility by HMT was correlated with PAK-1-mediated inhibition of Lim domain kinase (LIMK) and cofilin. HMT induced G1 arrest and apoptosis through the transcriptional regulation of cell cycle regulatory proteins and apoptosis-related proteins (increase in c-cas3 and inhibition of PARP and BCL-2). Moreover, HMT suppressed PAK-1 expression, leading to the inhibition of AKT activities. Finally, we showed that decursin was the active ingredient involved in the inhibitory effect of HMT on PAK-1. Our findings demonstrated that HMT exerts its anticancer influence through the inhibition of PAK-1. The HMT formula could be applied in various fields, including functional health food and pharmaceutical development.

Background: We have previously reported the anti-hepatic lipogenic effect of fermented Rhus verniciflua stokes extract (FRVE) in an oleic-acid-treated HepG2 cell model. Methods: Herein, we advanced our understanding and evaluated the impact of FRVE in HFD-fed C57BL/6 mice using an animal model of nonalcoholic fatty liver disease (NAFLD). Milk thistle extract was used as a positive control to compare the effects of FRVE. Results: FRVE decreased body weight, intra-abdominal fat weight, and liver weight. Furthermore, FRVE decreased HFD-induced elevated serum levels of ALT, AST, TC, and TG, and downregulated the increase in hepatic lipid accumulation and TG levels. FRVE reduced hepatic SREBP-1, PCSK-9, SREBP-2, and ApoB mRNA levels. IHC data showed that FRVE reduced the levels of nucleic SREBP-1, increased the levels of LDLR, and upregulated the expression of p-AMPK. Conclusion: Overall, these results demonstrate the anti-hepatic lipidemic effect of FRVE in an animal model. These findings are consistent with our previous study and strongly suggest that FRVE exerts anti-hepatic lipogenic effects by activating AMPK.

Fomes fomentarius, an edible mushroom, is known to have anti-cancer, anti-inflammatory, and anti-diabetes effects. However, the underlying anti-cancer mechanism of F. fomentarius is unknown. To determine the molecular mechanism of the anti-cancer effects of F. fomentarius, various methods were used including fluorescence-activated cell sorting, Western blotting, migration, and crystal violet assays. F. fomentarius ethanol extract (FFE) decreased cell viability in six cancer cell lines (MDA-MB-231, MCF-7, A549, H460, DU145, and PC-3). FFE decreased the migration of MDA-MB-231 cells without causing cell toxicity. Furthermore, FFE attenuated the expression of matrix metalloproteinase-9 and phosphorylation of Akt as well as increased E-cadherin in MDA-MB-231 cells. FFE arrested the S and G2/M populations by inhibiting the expression of cell cycle regulatory proteins such as cyclin-dependent kinase 2, cyclin A/E, and S-phase kinase-associated protein 2. FFE increased the sub-G1 population and expression of cleaved caspase-9, -3, and cleaved poly adenosine diphosphate (ADP-ribose) polymerase at 72 h and suppressed B-cell lymphoma 2. Interestingly, FFE and AKT inhibitors showed similar effects in MDA-MB-231 cells. Additionally, FFE contained betulin which inhibited p-AKT in MDA-MB-231 cells. Our findings demonstrate that FFE inhibits cell motility and growth and induces apoptosis by inhibiting the phsphoinositide 3- kinase /AKT pathway and caspase activation.

Hypoxia enhances cancer development in a solid tumor. Hypoxia-inducible factor-1 α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor that regulates tumor. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, anti-apoptosis and cell proliferation as well as imparts resistance to cancer treatment. In this study, we assessed Crataegus Pinnatifida Bunge var. typical Schneider ethanol extract (CPE) for its anti-cancer effects in hypoxia-induced DU145 human prostate cancer cell line. CPE decreased the abundance of HIF-1α and sphingosine kinase-1 (SPHK-1) in hypoxia-induced prostate cancer DU145 cells. CPE decreased HIF-1α and SPHK-1 as well as SPHK-1 activity. Chlorogenic acid (CA) is one of four major compounds of CPE. Compared to CPE, CA significantly decreased the expression of HIF-1α and SPHK-1 as well as SPHK-1 activity in hypoxia-induced DU145 cells. Furthermore, CA decreased phosphorylation AKT and GSK-3β, which are associated with HIF-1α stabilization and affected SPHK-1 in a concentration-dependent manner. We confirmed the mechanism of CA-induced inhibition of HIF-1α by SPHK-1 signaling pathway using SPHK-1 siRNA and SPHK inhibitor (SKI). CA decreased the secretion and cellular expression of VEGF, thus inhibiting hypoxia-induced angiogenesis. Treatment of DU145cells with SPHK1 siRNA and CA for 48 h decreased cancer cell growth, and the inhibitory action of SPHK siRNA and CA on cell growth was confirmed by decrease in the abundance of Proliferating cell nuclear antigen (PCNA).

Lambertianic acid (LA) is known to have anti-allergic and antibacterial effects. However, the anticancer activities and mechanism of action of LA have not been investigated. Therefore, the anticancer effects and mechanism of LA are investigated in this study. LA decreased not only AR protein levels, but also cellular and secretory levels of PSA. Furthermore, LA inhibited nuclear translocation of the AR induced by mibolerone. LA suppressed cell proliferation by inducing G1 arrest, downregulating CDK4/6 and cyclin D1 and activating p53 and its downstream molecules, p21 and p27. LA induced apoptosis and the expression of related proteins, including cleaved caspase-9 and -3, c-PARP and BAX, and inhibited BCl-2. The role of AR in LA-induced apoptosis was assessed by using siRNA. Collectively, these findings suggest that LA exerts the anticancer effect by inhibiting AR and is a valuable therapeutic agent in prostate cancer treatment.