**4. Properties of flavonoids: an emphasis in their anticancer potential**

In plants, flavonoids are specialized metabolites that display several functions: defense against predators, protection against elements of biotic and abiotic stress, signaling molecules, detoxifying agents, growth regulators, inhibitors of protein components of pathogens, among others [34]. In human health, their antioxidant effects and vast pharmacological properties have driven their application in treating and preventing diseases, such as cancer, cardiovascular diseases, gastrointestinal disorders, and microbial infections. In addition, their anti-allergic, anti-inflammatory, antidiabetic, neuro, hepatic, and gastroprotective are attractive properties to the scientific community [35].

Flavonoids are convenient in cancer therapy because they can induce cytotoxicity on multidrug-resistant cancer cell lines, inhibit the transcription of oncogenes, ATP-dependent efflux pumps (i.e., P-glycoprotein), and glucose transporters [36].

The anticancer effects of flavonoids are due to their capacity to target major signaling pathways such as nuclear factor kappa B (NF-κB), mitochondrial, and phosphatidylinositol-3-kinase (PI3K) pathways.

Besides, flavonoids inhibit cytochrome P450 (CYPs) enzymes (e.g., CYP1B1 and CYP1A) entailed in the metabolism of anticancer drugs [37]. Flavonoids such as fisetin, robinetin, myricetin, eupafolin, and hispidulin, are widely used to delay carcinogenesis, promote cytoprotection, genoprotection, and interfere with inflammatory and oxidative mechanisms *in vitro* and *in vivo* [38].

Inflammation plays a significant role in the evolution and potentiation of cancer invasion by increasing the production of reactive oxygen species (ROS), leading to oxidative DNA damage and reducing DNA repair. The abundance of other components such as chemokines or pro-inflammatory cytokines (e.g., tumor necrosis factor-; TNF-) leads to cancer progression, angiogenesis, and neoplastic growth.

Overproduction of immune cells such as macrophages, mast cells, neutrophils, and T lymphocytes also contributes to cancer malignancy by releasing extracellular proteases, pro-angiogenic factors, inflammatory mediators, and favoring tumor microenvironment architecture [39].

Flavonoids regulate these events owing to their antioxidative and radical scavenging activities. Such NPs also modulate the production and gene expression of pro-inflammatory molecules, inflammation-related cells, and arachidonic acid metabolism enzymes activities [40]. In LC cells, many categories of flavonoids promote the activation of apoptosis and autophagy, cell adhesion, inhibit cell proliferation, retard invasion, impede metastasis, down-regulate epithelial-mesenchymal transition (EMT) in the tumor microenvironment, arrest cell cycle, and target cell signaling pathways. For this reason, it is possible to find the anti-lung cancer properties of various flavonoids in contemporary literature, such as apigenin, diosmetin, quercetin, hesperidin, catechin, genistein, and malvidin [39, 40]. In addition, luteolin, naringenin, kaempferol, and baicalein are flavonoids distributed on accessible natural sources, such as fruits, beverages, and plants.
