Pterostilbene Decreases the Antioxidant Defenses of Aggressive Cancer Cells In Vivo: A Physiological Glucocorticoids- and Nrf2-Dependent Mechanism
Por:
Benlloch M, Obrador E, Valles SL, Rodriguez ML, Sirerol JA, Alcácer J, Pellicer JA, Salvador R, Cerdá C, Sáez GT and Estrela JM
Publicada:
10 jun 2016
Resumen:
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.
Filiaciones:
Benlloch M:
1 Department of Health and Functional Valorization, San Vicente Martir Catholic University , Valencia, Spain
Obrador E:
2 Department of Physiology, University of Valencia , Valencia, Spain
Valles SL:
2 Department of Physiology, University of Valencia , Valencia, Spain
Rodriguez ML:
2 Department of Physiology, University of Valencia , Valencia, Spain
Sirerol JA:
2 Department of Physiology, University of Valencia , Valencia, Spain
Alcácer J:
3 Pathology Laboratory, Quirón Hospital , Valencia, Spain
Pellicer JA:
2 Department of Physiology, University of Valencia , Valencia, Spain
Salvador R:
2 Department of Physiology, University of Valencia , Valencia, Spain
Cerdá C:
4 Service of Clinical Analysis-CDB, General University Hospital, University of Valencia , Valencia, Spain
:
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
Estrela JM:
2 Department of Physiology, University of Valencia , Valencia, Spain
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