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Abstract Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.

Following ingestion of fruits, vegetables and derived products, (poly)phenols that are not absorbed in the upper gastrointestinal tract pass to the colon, where they undergo microbiota-mediated ring fission resulting in the production of a diversity of low molecular weight phenolic catabolites, which appear in the circulatory system and are excreted in urine along with their phase II metabolites. There is increasing interest in these catabolites because of their potential bioactivity and their use as biomarkers of (poly)phenol intake. Investigating the fate of dietary (poly)phenolics in the colon has become confounded as a result of the recent realisation that many of the phenolics appearing in biofluids can also be derived from the aromatic amino acids, l-phenylalanine and l-tyrosine, and to a lesser extent catecholamines, in reactions that can be catalysed by both colonic microbiota and endogenous mammalian enzymes. The available evidence, albeit currently rather limited, indicates that substantial amounts of phenolic catabolites originate from phenylalanine and tyrosine, while somewhat smaller quantities are produced from dietary (poly)phenols. This review outlines information on this topic and assesses procedures that can be used to help distinguish between phenolics originating from dietary (poly)phenols, the two aromatic amino acids and catecholamines.

The consumption of black garlic has been related to a decreased risk of many human diseases due to the presence of phytochemicals such as organosulfur compounds (OSCs). However, information on the metabolization of these compounds in humans is limited. By means of ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS), this study aims to determine the OSCs and their metabolites excreted in urine 24 h after an acute intake of 20 g of black garlic by healthy humans. Thirty-three OSCs were identified and quantified, methiin (17,954 ± 6040 nmol), isoalliin (15,001 ± 9241 nmol), S-(2-carboxypropyl)-L-cysteine (8804 ± 7220 nmol) and S-propyl-L-cysteine (deoxypropiin) (7035 ± 1392 nmol) being the main ones. Also detected were the metabolites N-acetyl-S-allyl-L-cysteine (NASAC), N-acetyl-S-allyl-L-cysteine sulfoxide (NASACS) and N-acetyl-S-(2-carboxypropyl)-L-cysteine (NACPC), derived from S-allyl-L-cysteine (SAC), alliin and S-(2-carboxypropyl)-L-cysteine, respectively. These compounds are potentially N-acetylated in the liver and kidney. The total excretion of OSCs 24 h after the ingestion of black garlic was 64,312 ± 26,584 nmol. A tentative metabolic pathway has been proposed for OSCs in humans.

The aim of this study was to investigate comprehensively the metabolic pathways and human bioavailability of anthocyanins and other (poly)phenols in an apple matrix, and to elucidate potential intake biomarkers. After the acute intake of a red-fleshed apple freeze-dried snack, plasma and urine were collected and analyzed by UPLC-MS/MS. A total of 37 phase-II and microbial phenolic metabolites were detected in plasma and urine. Among these, phloretin glucuronide, cyanidin-3-O-galactoside (plasma and urine) and peonidin-3-O-galactoside (urine) were the only metabolites detected in all the volunteers and not detected at basal conditions. The maximum urine excretion was detected at 2–4 h, and the main increase in plasma of phloretin glucuronide and cyanidin-3-O-galactoside was observed at 2 h post-intake (61.0 ± 6.82 and 10.3 ± 1.50 nM, respectively). These metabolites could be selected as the best intake biomarkers of red-fleshed apple and might be useful in human intervention studies when studying its health effects.

A total of 17 (poly)phenolic compounds have been quantified in the free and bound fraction of raw, olive oil fried, sunflower oil fried and griddled cardoon (Cynara cardunculus L.). Caffeoylquinic acid derivatives (CQAs), particularly 5-CQA, were the major compounds. The bioaccessibility of (poly)phenols after gastrointestinal digestion and fecal fermentation (24 h) was studied. Heat treatment exerted a positive effect on the bioaccessibility of (poly)phenols. In raw cardoon, only 2% of the total amount of (poly)phenolic compounds was still bioaccessible after gastrointestinal digestion, while in cooked cardoon samples, between 60 and 67% of the total amount of (poly)phenolic compounds remained unmodified. An important microbial metabolic activity was observed during the fecal fermentation, which resulted in a complete degradation of CQAs after 5 h and in the formation of different catabolites. 3-(3′-hydroxyphenyl)propionic acid was by far the most abundant catabolite produced. Catabolic pathways for colonic microbial degradation of CQAs of cardoon have been proposed.

A total of 21 (poly)phenolic compounds (free and bound) were quantified in raw, olive oil fried, sunflower oil fried and griddled green pepper before and after a simulated gastrointestinal digestion. Flavonoids, particularly quercetin rhamnoside, were the main compounds. The bioaccessibility of (poly)phenolic compounds after gastrointestinal digestion was higher in cooked (>82%) than in raw (48%) samples, showing a positive effect of heat treatment on the release of (poly)phenols from the vegetal matrix. Additionally, a faecal fermentation was carried out for 24h. A time-dependent microbial metabolic activity was observed, which resulted firstly (