Pterostilbene, A Natural Phytoalexin, Weakens The Antioxidant Defenses Of Aggressive Cancer Cells In Vivo: A Pituitary Gland- And Nrf2-Dependent Mechanism

Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies lack of correlation to the bioavailable concentrations is a critical issue. We studied the underlying mechanisms using different human melanomas (A2058, MeWo and MelJuso) and pancreatic cancers (AsPC-1 and BxPC-3) (with genetic backgrounds correlating with most tumors in patients), growing in nude mice as xenografts, and pterostilbene (Pter, 3’,5’-dimethoxy-4-stilbenol; abundant in e.g. blueberries and a natural dimethoxylated analog of resveratrol). RESULTS: Intravenous administration of Pter decreased human melanoma and pancreatic cancer growth (an effect associated with lower rates of tumor cell proliferation and increased apoptosis) in vivo. However Pter, at levels measured within the tumors, did not affect cancer growth or viability in vitro. Pter inhibited pituitary production of the adrenocorticotropin hormone (ACTH), decreased plasma levels of corticosterone and, thereby, down regulated the glucocorticoid receptor- and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent antioxidant defense system in growing cancers (i.e. the glutathione and thioredoxin systems, superoxide dismutases, catalase, and NADPH supplying dehydrogenases). Exogenous corticosterone or genetically-induced Nrf2 overexpression in the cancer cells prevented the inhibition of tumor growth and antioxidant defenses in these malignant cells. Glutathione depletion (selected as a potential anti-cancer strategy) facilitated the complete elimination by chemotherapy of cancer cells isolated from mice treated with Pter. CONCLUSIONS: This report shows a novel link between a neuroendocrine system- and stress response-dependent mechanism and the regulation of cancer growth in vivo. Natural polyphenols can interfere with the growth and defense of cancer cells by down-regulating the pituitary gland-dependent ACTH synthesis. Lower levels of plasma ACTH cause a decrease in the suprarenal glands-dependent glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells. Hence facilitating identification of molecular targets to sensitize aggressive cancers to oncotherapy. Citation Format: Maria Benlloch, Soraya L. Valles, Maria L. Rodriguez, J. Antoni Sirerol, Javier Alcacer, Jose Pellicer, Rosario Salvador, Concha Cerda, Guillermo T. Saez, Jose M. Estrela. Pterostilbene, a natural phytoalexin, weakens the antioxidant defenses of aggressive cancer cells in vivo: a pituitary gland- and Nrf2-dependent mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2810.