Studies of the antitumor activity of [alpha]-TEA in human breast cancer cells
Breast cancer is the most common cancer among women and is the second leading cause of cancer deaths among women in the United States. An effective chemotherapeutic drug is greatly needed for breast cancer. In order to develop a stable and clinically useful vitamin E-based chemotherapeutic agent, a nonhydrolyzable ether linked acetic acid analogue of RRR-a-tocopherol, namely, a-TEA has been produced. a-TEA exhibits strong antitumor activity in tumor cells but has no effect on normal cells. Since a-TEA is hydrophobic, formulation into appropriate carrier systems to potentiate delivery is needed. The anticancer efficacy of a-TEA formulated into liposomes or nanoparticles has been assessed in this study. a-TEA formulated in either nanoparticles or liposomes at 5 mg/day was very effective in inhibiting tumor growth and visible lung metastases, as well as lung and lymph node micrometastatic lesions. a-TEA at 2.5 mg/day formulated in nanoparticles was more effective than a-TEA at 2.5 mg/day formulated in liposomes in reducing tumor burden and lymph node and lung micro-metastatic tumor foci; however, the difference could be attributed to a nanoparticle effect rather than an a-TEA effect since nanoparticles alone significantly reduced tumor burden and metastases. These studies show that oral delivery of a-TEA at an appropriate dosage formulated in either liposomes or nanoparticles to be effective, clinically relevant means for administrating this hydrophobic drug. In the mechanistic studies of a-TEA, over 400 potential targets have been identified in a-TEA treated MDA-MB-435 cells using microarray analyses. Thirty four genes were of interest for their possible involvement in the known biological activities of a-TEA. Three genes, Arg, TSP-1 and NOXA were further studied. The proapoptotic BH3 only protein NOXA was studied in detail. Data show that NOXA induction was involved in a-TEA-induced mitochondria-dependent apoptosis in human breast cancer cells and NOXA expression was mediated through JNK-p73 signaling pathway. From the data reported in this thesis, we now have a better understanding of how a-TEA functions as a promising anticancer drug, and more importantly, how to efficiently use it as a chemotherapeutic reagent.