Melanoma

Neoplasia.2005 Jan;7(1):37-47.

Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.

Ferrer P¹, Asensi M, Segarra R, Ortega A, Benlloch M, Obrador E, Varea MT, Asensio G, Jordá L, Estrela JM.

Abstract

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.

PMID: 15736313

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.

Ferrer P¹, Asensi M, Priego S, Benlloch M, Mena S, Ortega A, Obrador E, Esteve JM, Estrela JM.

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Abstract

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.

PMID: 17135264

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.

Schneider JG¹,Alosi JA, McDonald DE, McFadden DW.

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Abstract

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.

PMID: 19887199

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.

Benlloch M¹,Obrador E², Valles SL², Rodriguez ML², Sirerol JA², Alcácer J³, Pellicer JA², Salvador R², Cerdá C⁴, Sáez GT^4,5, Estrela JM².

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Abstract

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.

PMID: 26651028