title: Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1 Department of Health and Functional Valorization, San Vicente Martir Catholic University , Valencia, Spain .
authors.forename: María
authors.initials: M
authors.lastname: Benlloch
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: Elena
authors.initials: E
authors.lastname: Obrador
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: Soraya L
authors.initials: SL
authors.lastname: Valles
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: María L
authors.initials: ML
authors.lastname: Rodriguez
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: J Antoni
authors.initials: JA
authors.lastname: Sirerol
authors.affiliation: 3 Pathology Laboratory, Quirón Hospital , Valencia, Spain .
authors.forename: Javier
authors.initials: J
authors.lastname: Alcácer
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: José A
authors.initials: JA
authors.lastname: Pellicer
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: Rosario
authors.initials: R
authors.lastname: Salvador
authors.affiliation: 4 Service of Clinical Analysis-CDB, General University Hospital, University of Valencia , Valencia, Spain .
authors.forename: Concha
authors.initials: C
authors.lastname: Cerdá
authors.affiliation: 4 Service of Clinical Analysis-CDB, General University Hospital, University of Valencia , Valencia, Spain .|5 Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology-INCLIVA, Service of Clinical Analysis, Dr. Peset University Hospital, University of Valencia , Valencia, Spain .
authors.forename: Guillermo T
authors.initials: GT
authors.lastname: Sáez
authors.affiliation: 2 Department of Physiology, University of Valencia , Valencia, Spain .
authors.forename: José M
authors.initials: JM
authors.lastname: Estrela
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D010084:Oxidation-Reduction; D013267:Stilbenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D005938:Glucocorticoids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D013267:Stilbenes; C107773:pterostilbene; D000324:Adrenocorticotropic Hormone