Synergistic Inhibition of Prostate Cancer Progression in Mice With a Combination of Curcumin and Ursolic Acid in the Diet.

Prostate cancer (PCa) is the second leading cause of cancer-related death among American men, and its long latency offers a window for chemopreventive strategies. Phytochemicals, with their diverse impacts on cancer cell growth and metabolism, represent promising candidates for such strategies. Combining compounds like curcumin (Curc) and ursolic acid (UA), which target multiple pathways, can be advantageous in slowing tumor progression. Previous studies revealed the synergistic effects of Curc + UA in reducing tumor growth in a PCa allograft model. In this study, diet-based interventions were evaluated using two transgenic mouse models of PCa. Mice fed a Curc + UA-enriched diet exhibited significant inhibition of prostate tumor progression compared to single-agent diets in both HiMyc and PTEN knockout mouse models. Protein analyses of ventral prostate tissues from HiMyc mice indicated that the combination suppressed oncogenic signaling pathways, including STAT3, AKT, and mTORC1, while modulating cell regulatory proteins to inhibit tumor cell proliferation. Furthert mechanistic studies in mouse and human PCa cell lines confirmed that Curc + UA exerted pleiotropic effects by influencing oncogenic signaling, cell cycle regulation, mitochondrial function, unfolded protein response (UPR), and apoptosis, collectively contributing to its synergistic efficacy. These findings highlight the potential of Curc + UA to inhibit PCa progression through multitargeted mechanisms. The combination's superior efficacy over single agents underscores its promise as a chemopreventive or therapeutic strategy. This study provides a strong rationale for further mechanistic investigations and clinical development of Curc + UA for PCa prevention and treatment.