Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.
Inhibition of cancer growth by resveratrol (trans-3,5,4′-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PTER) and quercetin (3,3′,4′,5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.
J Biol Chem.2007 Feb 2;282(5):2880-90. Epub 2006 Nov 29.
Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma.
Intravenous administration to mice of trans-pterostilbene (t-PTER; 3,5-dimethoxy-4′-hydroxystilbene) and quercetin (QUER; 3,3′,4′,5,6-pentahydroxyflavone), two structurally related and naturally occurring small polyphenols, inhibits metastatic growth of highly malignant B16 melanoma F10 (B16M-F10) cells. t-PTER and QUER inhibit bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. However, the molecular mechanism(s) linking polyphenol signaling and bcl-2 expression are unknown. NO is a potential bioregulator of apoptosis with controversial effects on Bcl-2 regulation. Polyphenols may affect NO generation. Short-term exposure (60 min/day) to t-PTER (40 microM) and QUER (20 microM) (approximate mean values of the plasma concentrations measured within the first hour after intravenous administration of 20 mg of each polyphenol/kg) down-regulated inducible NO synthetase in B16M-F10 cells and up-regulated endothelial NO synthetase in the vascular endothelium and thereby facilitated endothelium-induced tumor cytotoxicity. Very low and high NO levels down-regulated bcl-2 expression in B16M-F10 cells. t-PTER and QUER induced a NO shortage-dependent decrease in cAMP-response element-binding protein phosphorylation, a positive regulator of bcl-2 expression, in B16M-F10 cells. On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells. Direct NO-induced cytotoxicity and ceramide-induced mitochondrial permeability transition and apoptosis activation can explain the increased endothelium-induced death of Bcl-2-depleted B16M-F10 cells.
Am J Surg.2009 Nov;198(5):679-84. doi: 10.1016/j.amjsurg.2009.07.014.
Effects of ppterostilbene onmelanoma alone and in synergy with inositol hexaphosphate.
BACKGROUND: Pterostilbene and inositol-6-phosphate (IP6) have been shown to inhibit melanoma growth in vitro. However, pterostilbene’s mechanism of action has not been clearly demonstrated. We aimed to further investigate the mechanism of action for pterostilbeneand to determine whether combination treatment with IP6 produced synergistic growth inhibition.
METHODS: Melanoma cells were treated with increasing doses of pterostilbene, IP6, or combinations thereof. Cell viability was measured at 24 hours, 48 hours, and 72 hours using a MTT assay. Caspase activity and vascular endothelial growth factor (VEGF) production were measured using enzyme-linked immunosorbent assay (ELISA). Analysis of variance (ANOVA) and t tests were used for statistical analysis.
RESULTS: Pterostilbeneinhibits melanoma growth in vitro in association with increased effector caspase activity. Combination treatment with inositol hexaphosphate produces synergistic growth inhibition, greater than either treatment alone.
CONCLUSIONS: Pterostilbeneproduces caspase-dependent apoptosis in melanoma cell lines. Combination treatment with IP6 produces synergistic growth inhibition. Both compounds have significant potential for a therapeutic role in the treatment of melanoma.
Asian Pac J CancerPrev.2014;15(3):1163-9.
Enhanced antitumor efficacy with combined administration of astragalus and pterostilbene for melanoma.
Astragalus, a commonly used traditional Chinese medicine, has exhibited antitumor actions in patients. In this study, in vitro and in vivo antitumor effects of astragalus and synergistic antitumor efficacy in combination with pterostilbene were investigated. Melanoma cells were treated with pterostilbene (Pt), graduated doses of astragalus injection (AI), or these in combination. Cell viability was measured using a MTT assay. Released nucleosomes and caspase activity were measured using enzyme-linked immunosorbent assay. Growth inhibition in vitro and in vivo was also assessed. Analysis of variance and t tests were used for statistical analysis. Significant reduction (p<0.05) in cellular proliferation were observed with AI and AI-Pt in a time- and concentration-dependent manner. Apoptosis and caspase-3/7 activity were significantly increased by AI and AI-Pt treatment (p<0.05). In vivo, AI inhibited melanoma tumor growth, with inhibition rates ranging from 36.5 to 62.3%, by inducing apoptosis via up-regulation Bax expression and the Bax/Bcl-2 ratio and down-regulating Bcl-2 expression. AI significantly inhibits the growth of melanoma in vitro and in vivo by inducing apoptosis. These data suggest that combined treatment of astragalus with pterostilbene enhances antitumor efficacy.
Antioxid Redox Signal.2016 Jun 10;24(17):974-90. doi: 10.1089/ars.2015.6437. Epub 2016 Mar 15.
PterostilbeneDecreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism.
AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies, lack of correlation with the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules downregulate the stress response, which may affect growth and the antioxidant protection of malignant cells. Initially, we studied this potential underlying mechanism using different human melanomas (with genetic backgrounds correlating with most melanomas), growing in nude mice as xenografts, and pterostilbene(Pter, a natural dimethoxylated analog of resveratrol).
RESULTS: Intravenous administration of Pter decreased human melanoma growth in vivo. However, Pter, at levels measured within the tumors, did not affect melanoma growth in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone, and thereby downregulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing melanomas. Exogenous corticosterone or genetically induced Nrf2 overexpression in melanoma cells prevented the inhibition of tumor growth and decreased antioxidant defenses in these malignant cells. These effects and mechanisms were also found in mice bearing different human pancreatic cancers. Glutathione depletion (selected as an antimelanoma strategy) facilitated the complete elimination by chemotherapy of melanoma cells isolated from mice treated with Pter.
INNOVATION: Although bioavailability-related limitations may preclude direct anticancer effects in vivo, natural polyphenols may also interfere with the growth and defense of cancer cells by downregulating the pituitary gland-dependent ACTH synthesis.
CONCLUSIONS: Pter downregulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells. Antioxid. Redox Signal. 24, 974-990.