Prostate and breast cancer are the second leading cause of cancer death in American men and women respectively. About 1 man in 6 will be diagnosed with prostate cancer and 1 in 8 women will develop invasive breast cancer during their lifetime. Conventional treatments such as surgery and chemotherapy are available but with severe side effects. Recently, evidences from preclinical and clinical studies demonstrate the potential of pomegranate juice (PJ) as natural remedy to fight cancer. I took an integrative approach by using various cellular assays to study important cellular processes for metastasis, Affimetrix gene arrays to study gene expression, microRNA PCR arrays to study the non-coding RNAs, molecules known to be disregulated in cancer cells, and Luminex multiplex immunoassays to study the level of pro-inflammatory cytokines/chemokines. We found that, in addition to causing cell death, PJ increases cell adhesion and decreases cell migration of the prostate and breast cancer cells that do not die. PJ also inhibits the ability of the chemokine CXCL12, together with its receptor CXCR4 are critical in cancer metastasis, to chemoattract cancer cells. Since PJ is a very complex mixture of components, it is important to identify specific components that can mimic the effects of the juice. I found that the combination of a polyphenolic compound (luteolin/L), an antioxidant (ellagic acid/E) and a seed oil component (punicic acid/P), individually and in combination, synergistically affect processes critical for metastasis. L+E+P inhibits growth of prostate and breast cancer cells, their migration and their chemotaxis towards CXCL12. These components also increase the expression of cell adhesion genes and decrease expression of genes involved in cell migration and cell cycle control. The in vivo studies further support the potential of L+E+P. By using the Severely Combined Immuno-Deficiency (SCID) mouse model in which prostate cancer cells were injected subcutaneously, I show that L+E+P inhibits primary tumor growth, angiogenesis and, more importantly, significantly inhibits metastasis. Furthermore, I show that critical cellular processes for metastasis in human endothelial cells are affected by L+E+P. In conclusion, pomegranate and its components can potentially be used to prevent progression and metastasis of prostate and breast cancer.
|Commitee:||DeFea, Kathryn, Walker, Ameae|
|School:||University of California, Riverside|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- California|
|Source:||DAI-B 75/05(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Biochemistry, Organic chemistry, Oncology|
|Keywords:||Breast cancer, Cancer progression, Metastasis, Natural products, Pomegranate juice, Prostate cancer|
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