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Document Type

Thesis - University Access Only

Award Date

2013

Degree Name

Master of Science (MS)

Department

Chemistry and Biochemistry

First Advisor

Fathi Halaweish

Abstract

Hepatocellular Carcinoma (HCC) is the fourth leading cause of death worldwide. HCC is one major example of inflammatory-associated cancer. Aggressive resection or liver transplantation can successfully treat small or slow-growing tumors if they are diagnosed early. Chemotherapy and radiation treatments are not usually effective. They are mainly used to shrink a large tumor, so the resection can be done successfully. Thus, despite great strides made in therapy regimens, most treatments are destined to eventually fail. Prevention of tumor formation would be a powerful alternative for treatment. Cucurbitacins (Cucs) are natural triterpenoids known for their potent anticancer and antiinflammatory activities. Recent studies showed that Cucs protect the HepG2 cell line against CCl4 induced toxicity. The mechanism behind this cytoprotection is unknown. The hepatoprotective effect of cucurbitacin compounds might be due to the inhibition of TNF-α and IL-6, important inflammatory factors that connects inflammation and cancer. Previous reports demonstrated the role of TNF-α and IL-6 in tumor proliferation, migration, invasion and angiogenesis. TNF-α and IL-6 are produced due to the activation of IKK/ NF-kB pathway in liver cells. Identification of a cucurbitacin molecular target was achieved using in silico drug design approaches. Molecular docking of natural and virtual cucurbitacin analogs over NF-kB, and IKKβ crystal structures was conducted. Docking data revealed approximately 100 potential cucurbitacin analogs with higher binding affinity to the hydrophobic pocket of NF-kB and IKKβ compared to standard IKK inhibitor (PS-1145). Cucs B, D, and iso-D were isolated from Cucurbita texana and characterized using spectroscopic techniques. The effect of Cucs compounds on the production of TNF-α and IL-6 was analyzed by using colorimetric ELISA assays. The effect of Cucs compounds on the activation of NF-kB pathway was analyzed using in cell based NF-kB immunoassay. The result of the ELISA assays revealed that Cuc D and DHCD prevent the production of TNF-α and IL-6 from HSC-T6 cells. Cuc D and DHCD also showed significant inhibition of NF-kB activation compared with PS-1145. Thus, cucurbitacin D and DHCD had a significant hepatoprotective effects on the activated rat HSC-T6 cells due to inhibition of the production of TNF-α and IL6 through NF-kB pathway.

Library of Congress Subject Headings

Cancer -- Chemotherapy
Cucurbitaceae -- Therapeutic use
Plant toxins

Description

Includes bibliographical references (pages 66-73)

Format

application/pdf

Number of Pages

88

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

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