Pterostilbene decreases the antioxidant defenses of aggressive cancer cells in vivo - GreenMedInfo Summary
Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells in Vivo: a Physiological Glucocorticoids- and Nrf2-Dependent Mechanism.
Antioxid Redox Signal. 2015 Dec 9. Epub 2015 Dec 9. PMID: 26651028
AIMS: Polyphenolic phytochemicals have anticancer properties. However, in mechanistic studies lack of correlation to the bioavailable concentrations is a critical issue. Some reports had suggested that these molecules down-regulate 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, down regulated 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 anti-melanoma 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 down-regulating the pituitary gland-dependent ACTH synthesis.
CONCLUSIONS: Pter down-regulates glucocorticoid production, thus decreasing the glucocorticoid receptor and Nrf2-dependent signaling/transcription and the antioxidant protection of melanoma and pancreatic cancer cells.