Date of Award

5-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Nutritional Sciences

Major Professor

Jay Whelan

Committee Members

Guoxun Chen, Seung J. Baek, Michael F. McEntee

Abstract

The reductionist approach contributes greatly to our understanding of anticancer properties of phytonutrients, but in vitro studies demand concentrations that are 100-1000 times higher than achievable in humans, producing results with little physiologic relevance, resulting in disappointing outcomes in clinical trials. However, maintaining these bioactives in the presence of other compounds originally derived from the food/extract of origin may synergistically lower the bioactive dose so translatability becomes feasible. The first objective of this study was to determine if bioefficacy of phytonutrients can be enhanced when used in combination at doses that are ineffective when used in isolation. In this project, proliferation of CWR22Rv1cells, HEK293 cells and expression of NF-kappa B was evaluated and synergy were assessed using Chou-Talalay method when treated with turmeric, Chinese goldthread and their bioactives in isolation or in combination. Bioactives were not as potent as their extracts of origin. Combinations of herbal extracts and/or their isolated bioactives interacted synergistically and lowered effective concentrations to those similarly found in humans and may account for why foods/plant extracts are more likely to be beneficial against cancer compared with isolated components.

Turmeric and Chinese goldthread are two major components of a polyherbal mixture, Zyflamend, which has anti-prostate cancer (PCa) effects via multiple mechanisms. Zyflamend regulated fatty acid metabolism by inhibiting synthesis and enhancing oxidation in prostate cancer cells, suggesting AMP-activated protein kinase (AMPK), the master energy sensor of cells, as a potential target. Therefore, the second objective was to investigate whether the antiproliferative effects of Zyflamend were mediated via AMPK activation. Our results showed that in castrate resistant PCa cells, Zyflamend activated AMPK, and in turn, regulated known downstream targets of AMPK, such as mammalian target of rapamycin complex 1 (mTORC1) and the phosphorylation of acetyl CoA carboxylase (ACC). The anti-proliferative effects of Zyflamend could be mimicked by AMPK activation and attenuated by AMPK inhibition. Thus, we concluded that AMPK activation contributes to the anti-PCa effect of Zyflamend. These novel results, along with those published previously, provide a more complete picture of how this polyherbal mixture may complement conventional treatments based on its multiple mechanisms of action.

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