Stress, Inflammation, Cancer and Dementia; CDDO and Curcumin as Therapeutic Agents

Date of Award

2015

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Harold Komiskey, PhD

Second Advisor

Abigail Hielscher, PhD

Third Advisor

Eric Wang, PhD

Abstract

Millions of people around the world suffer from cancer and dementia, yet there remains no cure for either of these debilitating conditions. The lack of effective therapeutics has spurred a renewed interest in drugs derived from natural plants. For centuries, countries around the world have utilized plant-based compounds to treat people with dementia and cancer. Curcumin and CDDO-derived compounds are two of the most promising therapeutic agents that are naturally found and synthetically derived, respectively. The present study investigates the ability of curcumin and CDDO-methyl ester (CDDO-me) to regulate inflammation through the expression of mediators NF-κβ and Chitinase-3-like protein 1 (CHI3L1) in rat hippocampal embryonic astrocytes. We hypothesize that curcumin and CDDO-me protect astrocytes during ZnSO4 and H2O2 – induced oxidative stress by regulating the expression of NF-κβ and CHI3L1. This study also examines potential anti-cancer effects of curcumin and CDDO-me in multiple myeloma (MM) cancer cells. Based on current literature, both treatments should demonstrate time and dose- dependent responses in a two-dimensional setting (uncoated 48-well plate). However, to more accurately capture the in vivo environment, we have encapsulated MM cells into a 3-dimensional gelatin-based culture prior to drug treatment, where the drugs are still expected to demonstrate significant toxicity. Through these measures, we seek to determine whether curcumin and CDDO-me can protect ROS-induced oxidative-stressed astrocytes by regulating inflammatory mediators while effectively inducing cell death in MM cancer cells in both 2D and 3D microenvironments. By studying drug effects and their modes of action, we will gain a better understanding of the mechanisms that underlie neurodegenerative diseases and cancers. If these mechanisms can be identified, effective drugs can be designed to improve patient prognoses.

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