Food-related glycoaminoconjugates as potentially chemopreventive agents.

B108

Epidemiological studies suggest that the majority of human cancers could be prevented by lifestyle changes including dietary modification. Increased intake of vegetables and fruits that are rich in carbohydrates is consistently associated with lower cancer risk as compared to other diet modifications. Ketosamines (KAs) represent a class of glycoaminoconjugates found in processed foods such as dried fruits and vegetables, powdered milk, etc. Two principal carbohydrate residues in most of the naturally found KAs are fructose and lactulose. Respective aminoconjugates found in processed veggies are fructosamines and those found in dry milk are lactulosamines. These compounds possess a unique chemical structure that makes them candidates for evaluation of cancer chemoprevention potential. First, fructosamines may act as powerful antioxidants, via both copper/iron chelation and reduction of oxidating species. Second, lactulosamines structurally mimic tumor-associated carbohydrate antigens, such as TF-antigen, and strongly bind to tumor-associated lectins, such as galectins. Therefore, KAs, as follows from their chemical constitution, may target oxidative stress, tumor related antigens, cell adhesion and mitogenic lectins. We have investigated the anti-tumor potential of KAs against prostate and breast cancer using both in vitro and in vivo models. In vitro, fructosamines inhibited clonogenic growth of highly metastatic adenocarcinoma cell lines. KAs induced apoptosis in metastatic cells, triggered intracellular accumulation of reactive oxygen species and interacted with oxidative stress-inducing drugs, such as anthracyclines. Importantly, we have identified a specific fructosamine, related to tomato products, which strongly synergized with lycopene against the prostate tumor cell growth. Processed milk-related lactulosamines have demonstrated the ability to prevent cancer cell homotypic aggregation and galectin-dependent adhesion of cancer cells to endothelia, both in vitro and ex vivo. Galectin blocking by lactulosamine also protected activated T-lymphocytes. In vivo, these KAs showed significant inhibition of both primary tumors growth and metastatic lesions in the androgen-resistant Dunning 3327 rat prostate adenocarcinoma model, as well as human breast and prostate tumor xenograft murine models and enhanced efficiency of dendritic cell immunotherapy in a murine model. The therapeutic effects were observed in the KA-treated animals that obtained these glycoaminoconjugates both intraperitoneally and orally. The chemopreventive potential of a dietary KA in a rat prostate carcinogenesis model is currently under investigation; our preliminary observation is that a KA-treated group has a significantly higher survival rate as compared to the controls. Importantly, no toxicity or other side effects were detected over months of the KA treatments in any of the studied animal groups.