Araticum (Annona crassiflora) seed extract as a chemopreventive agent against prostate cancer: activation of extrinsic and intrinsic apoptotic pathways in a preclinical model

Prostate cancer (PCa) is among the most frequently diagnosed malignancies in aging men and remains a major public health concern, highlighting the need for effective and safe preventive strategies. Annona crassiflora Mart. seed extract (ASE) was evaluated using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Animals were divided into control and ASE-treated groups evaluated from 8–12 to 12–16 weeks of age. Control groups received the vehicle (water containing 10% DMSO), whereas ASE-treated groups received 100 mg/kg body weight of ASE. The preservation of hepatic histoarchitecture and normal body weight gain demonstrated that ASE was well tolerated and did not show hepatotoxic effects. ASE treatment increased the frequency of healthy prostatic epithelium in early prostate lesions (predominantly low-grade prostatic intraepithelial neoplasia (LGPIN)) and late prostate lesions (high-grade prostatic intraepithelial neoplasia (HGPIN) and well-differentiated adenocarcinoma (WDAC)) of PCa. Furthermore, ASE reduced HGPIN incidence in the ASE 12–16 group, showing a lower incidence of WDAC. In addition, ASE reduced androgen receptor (AR) protein levels as well as cytoplasmic and nuclear AR localization in late prostate lesions (HGPIN and WDAC) of PCa. ASE also induced apoptosis through multiple pathways, including upregulation of BID, BAD, and BAX, activation of caspase-8, caspase-9, and caspase-3, and downregulation of BCL-2, BCL-xL, and MCL-1. Thus, ASE promotes a pro-apoptotic environment unfavorable to tumor survival. Taken together, these results reinforce the potential of ASE to modulate prostatic homeostasis, indicating a promising strategy with chemopreventive effects and potential as an adjuvant therapy against PCa. Graphical Abstract