Jaboticaba Peel Extract Limits Castration-Resistant Prostate Cancer Aggressiveness by Counteracting EMT

Despite initial efficacy, androgen deprivation therapy (ADT) for prostate cancer (PCa) often leads to relapse, resulting in highly aggressive and metastatic castration-resistant prostate cancer (CRPC). A critical mechanism driving this progression and hormone resistance is epithelial-to-mesenchymal transition (EMT), a process where epithelial cells acquire mesenchymal characteristics, facilitating metastasis. Current treatments struggle against CRPC, particularly when tumors become double-negative (lacking androgen receptor and neuroendocrine activity). There is an urgent need for adjuvant strategies that can counteract EMT and modulate steroid hormone signaling to prevent CRPC progression.

Researchers investigated jaboticaba peel extract (JPE) as an adjuvant in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model of CRPC. Sixteen-week-old mice underwent surgical castration combined with chemical castration using 10 mg/Kg enzalutamide. This ADT regimen was administered alone or in combination with JPE at a dose of 5.8 g/Kg. Control groups included sham-castrated mice receiving either placebo or JPE. The primary endpoints focused on assessing the ratio of widespread prostatic tumors and evaluating protein levels of EMT markers using Western blot or similar protein analysis techniques.

JPE significantly impacted CRPC progression in the TRAMP model. In mice undergoing ADT, JPE reduced the ratio of widespread prostatic tumors, indicating a decrease in overall tumor burden and aggressiveness, although it did not affect metastases. Mechanistically, JPE treatment led to a reduction in the protein levels of the crucial EMT drivers ZEB1 and N-Cadherin. Furthermore, JPE contributed to the maintenance of a periacinar layer, primarily composed of smooth muscle cells, suggesting a preservation of tissue architecture that typically degrades during EMT. > JPE-induced effects in castrated mice involved a decrease of AR protein expression and beneficial ERβ actions, including a putative stimulation of TGF-β tumor-suppressive actions. This modulation of steroid hormone and TGF-β signaling pathways underscores a multi-pronged approach by JPE in hampering EMT and preventing poorly differentiated tumor progression.