No abstract

Wingless/integrase-11 (WNT)/β-catenin pathway is a crucial upstream regulator of a huge array of cellular functions. Its dysregulation is correlated to neoplastic cellular transition and cancer proliferation. Members of the Dishevelled (DVL) family of proteins play an important role in the transduction of WNT signaling by contacting its cognate receptor, Frizzled, via a shared PDZ domain. Thus, negative modulators of DVL1 are able to impair the binding to Frizzled receptors, turning off the aberrant activation of the WNT pathway and leading to anti-cancer activity. Through structure-based virtual screening studies, we identified racemic compound RS4690 (1), which showed a promising selective DVL1 binding inhibition with an EC50 of 0.74 ± 0.08 μM. Molecular dynamic simulations suggested a different binding mode for the enantiomers. In the in vitro assays, enantiomer (S)-1 showed better inhibition of DVL1 with an EC50 of 0.49 ± 0.11 μM compared to the (R)-enantiomer. Compound (S)-1 inhibited the growth of HCT116 cells expressing wild-type APC with an EC50 of 7.1 ± 0.6 μM and caused a high level of ROS production. These results highlight (S)-1 as a lead compound for the development of new therapeutic agents against WNT-dependent colon cancer.

Several pharmaceutical companies are nowadays considering the use of agri-food waste as alternative raw material for the extraction of bioactive compounds to include in nutraceuticals and food supplements. This recycling activity is encountering the support of authorities, which are alarmed by air, soil and water pollution generated by agricultural waste disposal. Waste reuse has several economic advantages: (i) its low cost; (ii) its abundance; (iii) the high content of bioactive molecule (antioxidants, minerals, fibers, fatty acids); as well as (iv) the financial support received by governments eager to promote eco-compatible and pollution-reducing practices. While nutraceuticals produced from biowaste are becoming popular, products that have been risk-assessed in terms of safety are quite rare. This despite waste biomass, in virtue of its chemical complexity, could, in many cases, mine the overall safety of the final nutraceutical product. In this review, we summarize the scientific results published on genotoxicity risk-assessment of bioactive compounds extracted from agricultural waste. The review depicts a scenario where the risk-assessment of biowaste derived products is still scarcely diffuse, but when available, it confirms the safety of these products, and lets us envisage their future inclusion in the list of botanicals allowed for formulation intended for human consumption.

Agri-food by-products represent a considerable portion of the waste produced in the world and especially when incorrectly disposed of, contribute to air, soil, and water pollution. Recently, recycling of food waste has proven to be an attractive area of research for pharmaceutical companies, that use agri-food by-products (leaves, bark, roots, seeds, second-best vegetables) as alternative raw material for the extraction of bioactive compounds. Developers and producers are however, advised to assess the safety of nutraceuticals obtained from biowaste that, in virtue of its chemical complexity, could undermine the overall safety of the final products. Here, in compliance with EFSA regulations, we use the Ames test (OECD 471) and the micronucleus test (OECD 487) to assess the mutagenicity of two nutraceuticals obtained from food waste. The first consists of grape seeds (Vitis vinifera L.) that have undergone a process of food-grade depolymerization of proanthocyanidins to release more bioavailable flavan-3-ols. The second nutraceutical product consists of thinned nectarines (Prunus persica L. var nucipersica) containing abscisic acid and polyphenols. The results presented here show that these products are, before as well as after metabolization, non-mutagenic, up to the doses of 5 mg and 100 μg per plate for the Ames and micronucleus test, respectively, and can be thus considered genotoxically safe.