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

• Published in: Biomedicine & pharmacotherapy Vol. 158; p. 114076
• Main Authors: Mostafa, Hamza, Behrendt, Inken, Meroño, Tomás, González-Domínguez, Raúl, Fasshauer, Mathias, Rudloff, Silvia, Andres-Lacueva, Cristina, Kuntz, Sabine
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2023
• Subjects: Adhesion molecules; Anthocyanins; Anthocyanins - pharmacology; Cell Line, Tumor; Cross-Over Studies; Endothelial Cells - metabolism; Healthy Volunteers; Humans; Metabolomics; Migration; NF-kappa B - metabolism; Pancreatic cancer cells; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Tandem Mass Spectrometry; Metabolomics; FAK; Pancreatic cancer cells; Migration; ROS; Anthocyanins; Adhesion molecules; HUVEC; TEER; ACN; CAM
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2022.114076

Pancreatic cancer is primarily considered to be a metastatic disease with a low 5-year survival rate. We aimed to detect if plasma-isolated anthocyanins and their metabolites (PAMs) modulate pancreatic cancer cells migration and to describe molecular targets of PAMs in this process. Plasma metabolites were isolated by solid-phase extraction before and after a 28-days intervention trial involving 35 healthy subjects comparing effects of a daily anthocyanin-rich juice intake vs. placebo. Plasma extracts were used for migration and mechanistic in vitro studies as well as for metabolomic analysis. Pancreatic PANC-1 and AsPC-1 were used for migration studies in a Boyden chamber co-cultured with endothelial cells. Expression of adhesion molecules on cancer and endothelial cells were determined by flow cytometry and NF-kB (nuclear factor-kappa B) p65 and focal adhesion kinase activation were measured by immunoassays. UHPLC-MS/MS metabolomics was done in plasma and urine samples. Plasma extracts isolated after the intake of the anthocyanin-rich juice significantly reduced PANC-1 migration, but not AsPC-1 migration. In PANC-1, and to a lower extent in endothelial cells, plasma extracts after juice intake decreased the expression of ß1- and ß4-integrins and intercellular adhesion molecule-1. Pooled plasma from volunteers with the highest inhibition of PANC-1 migration (n = 10) induced a reduction of NF-kB-p65 and FAK-phosphorylation in cancer and in endothelial cells. Concerning metabolites, 14 were significantly altered by juice intervention and PANC-1 migration was inversely associated with the increase of o-coumaric acid and peonidin-3-galactoside. PAMs were associated with lower PANC-1 cell migration opening new strategies for metastatic pancreatic cancer treatment. [Display omitted] •Pancreatic cancer cells are characterized by early and invasive metastatic potential.•Plasma extracts after ACN intake reduced PANC-1 migration.•Plasma extracts inhibited the expression of CAMs via FAK and NF-KB pathways.•Microbial phenolic metabolites of ACNs were associated with PANC-1 migration.•ACNs-based strategies may help in metastatic pancreatic cancer treatment.