Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor's Name

Marcus S. Cooke

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Stanislaw Wnuk

Second Advisor's Committee Title

Co-Committee Chair

Third Advisor's Name

Changwon Yoo

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Quentin Felty

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

Helen Tempest

Fifth Advisor's Committee Title

Committee Member

Keywords

breast cancer, estrogen, E2, TPP, majorana, mitochondria, target-specific, biomolecule

Date of Defense

6-30-2017

Abstract

Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as PEGylated bioconjugate of OME with TPP (P-OME-TPP) against human breast epithelial and cancer cell lines was investigated. Initially, TPP, a lipophilic cation, was used to check whether an imbalance in mitochondrial bioenergetics, in part, may be responsible for estrogen induced growth of breast cancer. The results showed that exposure of estrogen-dependent MCF-7 cells to 17 β-estradiol (E2) induced the metabolic activity, proliferation, mitochondrial bioenergetics, DNA damage, and formation of cellular and mitochondrial reactive oxidant species (ROS). These E2-induced endpoints were inhibited by co-treatment with TPP, indicating mitochondrial mechanisms, in part, may contribute to the development of breast cancer. Furthermore, O. majorana, widely used in the Middle East as a culinary aromatic medicinal herb, has been shown to possess an extensive range of biological activity including antioxidant, anti-inflammatory, and anti-tumor growth effects. Interestingly, the anticancer potential of O. majorana against breast cancer remains largely unexplored; therefore, the anticancer effect of O. majorana on breast cell lines was investigated. The results showed that E2-induced metabolic activity and growth were inhibited by OME in MCF-7 cells. The results also demonstrated that synthesized P-OME-TPP conjugate, compared to OME, was far more effective in exerting its cytotoxic effect through the inhibition of growth and mitochondrial metabolic activity in both highly metastatic, triple negative MDA-MB-231 and estrogen-dependent MCF-7 breast cancer cells. Altogether, these findings offer a new perspective on the utility of mitochondria-targeted lipophilic TPP cation and the potential of O. majorana extract to be developed as a new therapy against breast tumors.

Identifier

FIDC001962

Available for download on Tuesday, July 24, 2018

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