Anti-metastatic potential of anthocyanins and their metabolites (metabotypes) on cancer cell lines with different phenotypes - role of intestinal fermentation and metabolization.
Final Report Abstract
Migration processes play a major role in tumor diseases. Cell adhesion molecules (CAM) on the surface of tumor cells and on the surface of endothelial cells, which are induced by the secretion of tumor cell-specific mediators, are primarily involved in this process. It is currently unclear whether anthocyanins (ACN) exert an influence on these processes. In view of the fact that ACN are strongly modified, the question arises as to whether native ACN or metabolites produced during fermentation by the microbiota or as part of systemic metabolism are responsible for possible effects. In order to close this knowledge gap, ACN and their metabolites (iPAM) were isolated from the plasma of healthy volunteers and their effects on various tumor cell lines of the pancreas (PANC-1 and AsPC-1 cells) and the colon (Caco-2 and HT-29 cells) were investigated. In the first phase of the project, an ACN-rich and ACN- poor juice was administered to healthy volunteers in an intervention study and iPAM (iPAMPlacebo and iPAMVerum) were isolated from the blood before and after juice intake. These were then used in the in-vitro cell studies and thus not only corresponded to physiological concentrations, but also represented the spectrum of metabolites originating from the fermentation. Metabolome analysis (LC-ESI-MS/HPLC-ESI-Q-ToF-MS) and microbiome analysis (16S rRNA sequence analysis) identified microbial metabolites as well as native ACN in plasma, urine and feces, which were associated with ACN uptake, but no influence of ACN on the α- and ß-diversity of the microbial community could be observed. Nevertheless, a cluster analysis revealed both positive and negative associations between metabolites associated with ACN metabolism and specific genera of the microbial community. In the second phase of the project, the iPAM were incubated with the tumor cells and investigated whether processes such as cell migration and the expression of cell adhesion molecules could be influenced. The results showed that the tumor cells not only express different levels of integrins and selectins, but also secrete tumor cell-specific mediators that influence CAM on endothelial cells differently. After incubation of the cells with iPAMVerum, the expression of integrins such as CD29, ICAM-1 and some CD49 isotypes was inhibited on both, tumor cells and stimulated endothelial cells. The migration of PANC-1 and HT-29 cells in the endothelial in-vitro migration model was also significantly inhibited by iPAMVerum. This inhibition occurred in an NF-B- as well as FAK-dependent manner. However, the results also show that the effects were associated with large inter-individual differences. The iPAMVerum of only a few subjects (socalled responders) were responsible for the inhibition of cell migration as well as for the inhibition of signaling pathways. In addition, an influence on the migration of HT-29 cells inhibited by chemotherapeutic agents could also be demonstrated in these so-called responders, but not by the so-called non-responders. In summary, the results obtained show that blood-derived ACN and their metabolites can influence tumor cell migration and expression of CAM. However, these effects are highly dependent on the tumor cell lines and the pattern of ACN and metabolites present in the blood after intestinal fermentation and metabolism. Thus, this project provides important insights into how the migration of tumor cells is influenced by nutritively absorbed compounds, as they also occur physiologically in the organism.
Publications
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Influence of Plasma-Isolated Anthocyanins and Their Metabolites on Cancer Cell Migration (HT-29 and Caco-2) In Vitro: Results of the ATTACH Study. Antioxidants, 11(7), 1341.
Behrendt, Inken; Röder, Isabella; Will, Frank; Mostafa, Hamza; Gonzalez-Dominguez, Raúl; Meroño, Tomás; Andres-Lacueva, Cristina; Fasshauer, Mathias; Rudloff, Silvia & Kuntz, Sabine
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Plasma anthocyanins and their metabolites reduce in vitro migration of pancreatic cancer cells, PANC-1, in a FAK- and NF-kB dependent manner: Results from the ATTACH-study a randomized, controlled, crossover trial in healthy subjects. Biomedicine & Pharmacotherapy, 158, 114076.
Mostafa, Hamza; Behrendt, Inken; Meroño, Tomás; González-Domínguez, Raúl; Fasshauer, Mathias; Rudloff, Silvia; Andres-Lacueva, Cristina & Kuntz, Sabine
