**6. Discussion**

Flavonoids constitute a broad group of secondary metabolites with fascinating pharmacological and nutraceutical properties. Since their discovery in the 1930s by Nobel Prize Dr. Albert Szent-Gyorgyi, many analytical methods have been settled to enlighten their chemical characteristics, differences with other subclasses of natural NP, quality, pharmacokinetics, and medicinal properties.

The anticancer and antioxidant activities of flavonoids are subjected to their structural organization, functional groups, and the total number and configuration of hydroxyl groups. For example, while the ortho-dihydroxy structure in the B-ring and the 2,3-double bond in conjugation with the 4-oxo function of the C-ring of luteolin is responsible for its antioxidant capacity [95]. In addition, the hydroxyl group at C3 in the C ring of kaempferol is important for its biological activity [96]. The hydroxyl group and moieties on the C7 atom in the structure of naringenin influences its antioxidant activity [97]. The antioxidant and anticancer activity of baicalein is attributed to seven double bonds in the two aromatic rings and three hydroxyls on ring A [97].

Screening therapeutic molecules against NSCLC is developed through *in vitro* and *in vivo* models. *In vitro* models include cancer cell lines and organoids; the former is a 3D classical helpful approach to expand our knowledge about the molecular and cell biology of various types of cancer in a limitless replicative manner [98]. This study alluded to several NSCLC cell lines, such as A549, LLC, NCI-460, NCI-H1299, NCI-H1975, NCI-H23, and NCI-H1650. However, other NSCLC cell lines include NCI-H358, TL-1, HCC4006, HCC827, and NCI-226 [99].

AEs, low solubility, cytotoxicity, incompatible pharmacokinetics, and drug resistance are significant drawbacks of NSCLC treatment. AEs are negative outcomes caused by medical interventions, some examples include prolongation of the hospital stay, injuries, side effects, or death [100]. On the other hand, drug resistance is an intrinsic or acquired serious concern that contributes to the growth, survival, chemoresistance, and evolution of NSCLC. This event occurs due to overexpression of receptors, increased cell signaling, mutations, and protein fusion. For example, the overexpression of EGFR and the fusion of ALK with echinoderm microtubuleassociated protein-like 4 (EML4) have been correlated with poor response to antibodies treatment, poor chemo-sensitivity, lower survival, lower response rate, NSCLC progression, and metastasis [101]. Therefore, a strategy to combat drug resistance is

*Shedding Light on Four Selected Flavonoids with Anti-non-small Cell Lung Cancer Properties DOI: http://dx.doi.org/10.5772/intechopen.105162*

the administration of two or more drugs. We found that the synergism of baicalein plus docetaxel is an effective, safe, non-toxic approach to induce cell cycle arrest at the G1 and G2/M phase, apoptotic events, and inhibit tumor growth angiogenesis in A549 and LLC cells.

On the other hand, the reports mentioned in this work identified that luteolin suppressed essential cell cycle regulators, such as cyclin D1 and cyclin D3. Such results are important because the overexpression of cyclin D1 and D3 is commonly associated with the evolution and progression of several types of cancer, including LC and NSCLC [102]. CDK4 and CDK6 are necessary proteins for the regulatory activity of cyclin D1 and cyclin D3. We described baicalein as a powerful flavone that, in combination with docetaxel, inhibited CDK4 and CDK6 expression. Inhibition of both proteins translated into the arrest of the cell cycle, down-regulation of CDC25C, cyclin B1, and -catenin on NSCLC models. We commented on the influence of naringenin on members of the caspase cascade (caspase-3 and -9) and the effect of kaempferol and its analogs on the inhibition of cellular regulators such as Nrf2.
