Synergistic inhibition of prostate tumor progression with a combination of curcumin and ursolic acid in the diet

Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. The long latency of PCa tumorigenesis provides ample opportunity for chemopreventive strategies to be applied. Generally, phytochemicals have diverse impacts on multiple pathways that can affect cancer cell growth and metabolism. Using combinations of compounds that target multiple receptors and pathways to slow tumor growth and progression represents an advantageous approach to chemoprevention. Our previous studies demonstrated that two phytochemicals, Curcumin (Curc) and ursolic acid (UA), exert synergistic effects on tumor growth in a xenograft model of PCa. In the current studies, we demonstrated that Curc+UA administered through the diet significantly inhibited prostate tumor progression in two transgenic mouse models of PCa compared to single agents. Analyses of protein isolated from the ventral prostate of these mice indicated that the combination reduced activation of oncogenic signaling pathways, including STAT3, AKT, and mTORC1 compared to controls. The combination also modulated critical cell regulatory proteins consistent with inhibition of tumor cell proliferation. Analyses of microRNA expression in tumors from HiMyc mice and in cultured PCa cells revealed significant decreases of members of the miR-17-92 and miR-106b-25 clusters, which are upregulated in PCa and have been shown to be involved in cell survival and tumor progression. Mechanistic studies in cultured mouse and human PCa cell lines further confirm the pleiotropic effects of the combination on oncogenic signaling, cell cycle, clonogenicity, mitochondrial function, unfolded protein response (UPR) activation, and apoptosis that contributed to the synergistic effects of Curc+UA on prostate tumor growth and progression in vivo. Collectively, the current data provide strong rationale for further mechanistic evaluation and clinical development of combining Curc+UA for the prevention and/or treatment of PCa.

Name thesis:degree_name

Doctor of Philosophy

Discipline thesis:degree_discipline

Translational Science

Grantor

The University of Texas at Austin

Year dc:date.issued

2024

Author dc:creator

• Friedman, Chelsea Alison

Advisor dc:contributor.advisor

• DiGiovanni, John

Committee members dc:contributor.committeemember

• Jill Hamilton-Reeves
• Stefano Tiziani
• James Fleet
• Pratap Kumar

• Chemoprevention
• Prostate cancer
• Natural compounds
• Phytochemicals

Language dc:language.iso

English

Identifier URI

https://doi.org/10.26153/tsw/64190

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/136888