Abstract

Pancreatic cancer is currently one of the most difficult diseases to treat due to difficulty of detection and the aggressive nature of the disease. In addition, pancreatic cancer has the highest mortality rates compared to other cancer types. These mortality rates are attributable in part to increasing resistance to cancer therapy. Cancer therapy resistance is caused by adaptations that favor survival within cancer cells and their environment, termed the tumor microenvironment. Intracellular adaptations include the overexpression of resistance-linked genes, such as the inhibitor of apoptosis (IAP) family of proteins and overall resistance to cell death. Adaptations in the tumor microenvironment include altered intercellular vesicular signaling through exosomes, resulting in tumor growth and progression. However, recent studies have shown that exosomes can also be used as a delivery mechanism for drugs with poor bioavailability, thus providing a therapeutic advantage for these compounds. Currently, researchers are moving toward a multi-dimensional approach to pancreatic cancer therapy that incorporates compounds that target crucial players in chemotherapy resistance and in the

tumor microenvironment, such as exosomes. Our studies are centered on the anti-cancer properties of curcumin, a turmeric derivative, on these intracellular and intercellular resistance mechanisms. The long term goal of this research is to determine the mechanisms by which curcumin modulates intracellular pathways related to pancreatic cancer survival and therapy resistance and exosome composition and release to improve the understanding of pancreatic cancer pathology and support the development of novel therapeutic approaches for pancreatic cancer patients. The specific objective of this research was to determine curcumin’s role in modulating intracellular proteins imperative for pancreatic cancer chemotherapy resistance such as the IAP proteins. Moreover, this research addressed the effects of curcumin on exosome release and function, specifically in the context of delivery to recipient pancreatic cancer cells. We have established that curcumin reduces expression of the IAPs in pancreatic cancer cells, inhibiting their survival and growth. Furthermore, curcumin not only attenuates pro-survival signaling through exosomes, but also itself carried within the nanovesicles and delivered to recipient pancreatic cancer cells, resulting in pancreatic cancer cell death.

LLU Discipline

Biochemistry

Department

Basic Sciences

School

School of Medicine

First Advisor

Wall, Nathan R.

Second Advisor

Casiano, Carlos A.

Third Advisor

Langridge, William H. R.

Fourth Advisor

Soto, Ubaldo

Fifth Advisor

Weldon, David J.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2015

Date (Title Page)

6-2015

Language

English

Library of Congress/MESH Subject Headings

Curcumin -- Pharmacology; Curcumin -- Physiology; Pancreatic Neoplasms -- Drug therapy; Carcinoma - Pancreatic Ductal -- Drug Therapy; Cell Survival -- Drug effects

Subject - Local

Pancreatic Cancer; Cancer Therapy Resistance; Tumor Microenvironment; Intracellular Adaptations; Resistance-linked Genes

Type

Dissertation

Page Count

124

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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