Wesley Taylor

Date of Award

Spring 2019

Document Type

Open Access Thesis

Department

Chemical Engineering

First Advisor

Ehsan Jabbarzadeh

Abstract

The paradigm shift in cancer treatments from traditional chemotherapeutics to targeted therapies has rapidly improved prognoses for patients for whom cancer was once a death sentence. This is especially true in the case of targeted immune therapies which activate the body’s own natural defense system to fight cancer. Despite these advances, however, cancer remains the second leading cause of death in the United States. The promise of targeted therapeutics has faced significant hurdles in providing effective cancer treatments, namely the limited percentage of susceptible cancers for each treatment, high cost burden, high toxicities, and significant risk of treatment induced resistance. As a result, targeted therapies are often combined into a cocktail of multiple drugs, including other targeted therapeutics and chemotherapies. These hurdles have led to a resurgence of interest in natural products to treat cancer. Natural products tend to be cheap, safe to use, and capable of targeting multiple cellular pathways at once. Multi- targeting natural products which simultaneously affect multiple cellular processes including angiogenesis, metastasis, immune response, and apoptosis are uniquely positioned to provide a robust treatment for cancer when used alone or in combination with current targeted therapeutics.

This study investigates the anticancer properties of two natural products, clusianone and deacetylnemorone. The compounds were screened against 60 cancer cell lines to determine the growth inhibitory properties of the compounds. Both compounds were found to inhibit cancer cell growth across all nine of the tissue types screened at doses of 10 µM or less. Clusianone subsequently induced cell death in 25 of the cell lines screened at 100 µM concentrations, while deacetylnemorone only induced cell death in one melanoma cell line SK-MEL-5 at 10 µM. Clusianone was further shown to target tubulin polymerization and induce dose dependent apoptosis in non-small cell lung cancer. The compounds were additionally assayed in vitro to determine their effects on angiogenesis, macrophage polarization, and cancer cell invasion. Both compounds were shown to reduce tube formation between endothelial cells, a crucial step in angiogenesis, and inhibit cancer cell invasion into cell free gaps. Finally, clusianone was shown to

increase the expression of TNF-�� and IL-6 in THP-1 derived macrophages, suggesting polarization to an M1, anticancer state. The multi-targeting nature described may allow these compounds to simultaneously induce cell death directly in tumor cells, starve tumors by reducing their blood supply, limit the invasion of cancers into healthy tissue, and stimulate the immune system to attack cancer cells. This multipronged attack would provide treatments which are less susceptible to resistance when used alone in addition to enhancing the effects of targeted therapies when used in combination. Clusianone and deacetylnemorone are therefore promising drug leads for anticancer therapy.

Rights

© 2019, Wesley Taylor

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