Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review

Abstract

Significance: Flavonoids can interact with multiple molecular targets to elicit their cellular effects, leading to changes in signal transduction, gene expression, and/or metabolism, which can, subsequently, affect the entire cell and organism. Immortalized cell lines, derived from tumors, are routinely employed as a surrogate for mechanistic studies, with the results extrapolated to tissues in vivo.Recent Advances: We review the activities of selected flavonoids on cultured tumor cells derived from various tissues in comparison to corresponding primary cells or tissues in vivo, mainly using quercetin and flavanols (epicatechin and (−)-epigallocatechin gallate) as exemplars. Several studies have indicated that flavonoids could retard cancer progression in vivo in animal models as well as in tumor cell models.Critical Issues: Extrapolation from in vitro and animal models to humans is not straightforward given both the extensive conjugation and complex microbiota-dependent metabolism of flavonoids after consumption, as well as the heterogeneous metabolism of different tumors.Future Directions: Comparison of data from studies on primary cells or in vivo are essential not only to validate results obtained from cultured cell models, but also to highlight whether any differences may be further exploited in the clinical setting for chemoprevention. Tumor cell models can provide a useful mechanistic tool to study the effects of flavonoids, provided that the limitations of each model are understood and taken into account in interpretation of the data.

The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective

“…For a detailed review of anticancer activity reported over the last 5 yr consult Zhou et al. () and on mechanisms of action see Kerimi & Williamson ().…”

Bioavailability of Quercetin in Humans with a Focus on Interindividual Variation

“…Quercetin safety has been critically reviewed (Harwood et al., ; Okamoto, ) and high‐purity quercetin was given Generally Recognized As Safe (GRAS) status in 2010 (FDA, ). Over the last few decades, many biological studies on quercetin have been published, reporting a wide range of biological effects in vitro and in vivo including anti‐inflammatory and neuroprotective activities (Boots, Haenen, & Bast, ; Dajas, ; Gibellini et al., ; Harwood et al., ; Kawabata, Mukai, & Ishisaka, ; Kerimi & Williamson, ; Okamoto, ; Russo, Spagnuolo, Tedesco, Bilotto, & Russo, ).…”

Cytochrome P450 CYP1 metabolism of hydroxylated flavones and flavonols: Selective bioactivation of luteolin in breast cancer cells

“…These compounds are ubiquitous in plant-based food products, such as fruits, vegetables and tea extracts and in medicinal plants. Their anticancer activity has been attributed to the inhibition of DNA damage, the inhibition of cell cycle associated proteins, the induction of apoptosis, the modulation of cell signaling pathways involved in proliferation and in the inhibition of carcinogenic metabolite formation (George et al, 2017;Curti et al, 2017;Kerimi et al, 2017;Clementino et al, 2017). The hydroxylated flavonoids apigenin, luteolin, quercetin and kaempferol are the main constituents of various dietary products and beverages and have been the focus of extensive research over the 6 last years.…”