Date of Award

9-2013

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

First Advisor

H. Xiao

Second Advisor

Eric A. Decker

Third Advisor

Lynne A. McLandsborough

Subject Categories

Molecular Biology

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Exclusively found in citrus peels, the inhibitory effects of polymethoxyflavones (PMFs) on 3 human non-small cell lung cancer cells have been investigated. Results showed that monodemethylated PMFs at 5-position potently inhibited lung cancer cells than those of their permethoxylated counterparts. The inhibition of cancer cells caused by monodemethylated PMFs was associated with both extensive cell cycle arrest and apoptosis as a result of modulation of key oncogenic signaling proteins. Treatment with different bioactive compounds in combination may enhance inhibitory effects on lung cancer due to their synergistic interaction among these agents. Results showed that both nobiletin/atorvastatin (NBT/ATST) and tangeretin/atorvastatin (TAN/ATST) co-treatments at low doses exerted strong synergy as confirmed by isobologram analysis, and also produced much stronger inhibitory effects on lung cancer cells in comparison to those produced by NBT, TAN, or ATST alone at higher doses. Flow cytometry analysis showed both NBT/ATST and TAN/ATST co-treatments significantly induced cell cycle arrest and apoptosis, and these molecular events were involved with prenylation of RhoA which subsequently resulted in alteration of key signaling proteins. Supplementation of mevalonate or geranylgeranyl pyrophosphate significantly counteracted the effects caused by NBT/ATST. Inhibitory effects of metabolites of PMFs against lung cancer cells were significantly stronger than those produced by their parental compounds. Treatments of PMFs significantly inhibited lung tumorsphere formation and aldehyde dehydrogenase bright cells implicating the potential utilization of these compounds to target lung cancer stem cells.

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