Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression-3PM pathways

Abstract

Inflammation is an essential pillar of the immune defense. On the other hand, chronic inflammation is considered a hallmark of cancer initiation and progression. Chronic inflammation demonstrates a potential to induce complex changes at molecular, cellular, and organ levels including but not restricted to the stagnation and impairment of healing processes, uncontrolled production of aggressive ROS/RNS, triggered DNA mutations and damage, compromised efficacy of the DNA repair machinery, significantly upregulated cytokine/chemokine release and associated patho-physiologic protein synthesis, activated signaling pathways involved in carcinogenesis and tumor progression, abnormal tissue remodeling, and created pre-metastatic niches, among others. The anti-inflammatory activities of flavonoids demonstrate clinically relevant potential as preventive and therapeutic agents to improve individual outcomes in diseases linked to the low-grade systemic and chronic inflammation, including cancers. To this end, flavonoids are potent modulators of pro-inflammatory gene expression being, therefore, of great interest as agents selectively suppressing molecular targets within pro-inflammatory pathways. This paper provides in-depth analysis of anti-inflammatory properties of flavonoids, highlights corresponding mechanisms and targeted molecular pathways, and proposes potential treatment models for multi-level cancer prevention in the framework of predictive, preventive, and personalized medicine (PPPM / 3PM). To this end, individualized profiling and patient stratification are essential for implementing targeted anti-inflammatory approaches. Most prominent examples are presented for the proposed application of flavonoid-conducted anti-inflammatory treatments in overall cancer management.

Supplementary information: The online version contains supplementary material available at 10.1007/s13167-021-00257-y.

Keywords: Cancer; Cancer initiation; Cancer progression; Cancer promotion; Carcinogenesis; Cytokines; DNA damage; Flavonoids; HIF-1α; IL-1β; IL-6; IL-8; Impaired healing; Inflammation; Inflammatory pathway; Low-grade systemic inflammation; Matrix metalloproteinases; Molecular targets; NF-κB signaling; Natural substances; Phytochemicals; Pre-metastatic niches; Predictive preventive personalized medicine (PPPM / 3PM); ROS; S100; Systemic hypoxic-ishemic effects; TNF-α; Tissue remodeling.

Fig. 1

Suppression of tumor initiation and promotion by flavonoids. Abbreviations: ↑ increased/activated; ↓ decreased/inhibited

Fig. 2

The effectiveness of flavonoids as anti-inflammatory agents against tumor progression. Abbreviations: ↑ increased/activated; ↓ decreased/inhibited