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Review
. 2021 Apr 2;26(7):2029.
doi: 10.3390/molecules26072029.

The Hallmarks of Flavonoids in Cancer

Luis Gustavo Saboia Ponte  1 , Isadora Carolina Betim Pavan  1   2 , Mariana Camargo Silva Mancini  1 , Luiz Guilherme Salvino da Silva  1 , Ana Paula Morelli  1 , Matheus Brandemarte Severino  1 , Rosangela Maria Neves Bezerra  1 , Fernando Moreira Simabuco  1
Affiliations
Review

The Hallmarks of Flavonoids in Cancer

Luis Gustavo Saboia Ponte et al. Molecules. .

Abstract

Flavonoids represent an important group of bioactive compounds derived from plant-based foods and beverages with known biological activity in cells. From the modulation of inflammation to the inhibition of cell proliferation, flavonoids have been described as important therapeutic adjuvants against several diseases, including diabetes, arteriosclerosis, neurological disorders, and cancer. Cancer is a complex and multifactor disease that has been studied for years however, its prevention is still one of the best known and efficient factors impacting the epidemiology of the disease. In the molecular and cellular context, some of the mechanisms underlying the oncogenesis and the progression of the disease are understood, known as the hallmarks of cancer. In this text, we review important molecular signaling pathways, including inflammation, immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle, and analyze the known mechanisms of action of flavonoids in cancer. The current literature provides enough evidence supporting that flavonoids may be important adjuvants in cancer therapy, highlighting the importance of healthy and balanced diets to prevent the onset and progression of the disease.

Keywords: cancer; cell signaling; flavonoids.

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Conflict of interest statement

The authors declare no potential conflict of interest.

Figures

Figure 1
Figure 1
The molecular actions of flavonoids in cell signaling in cancer. Flavonoids significantly alter the biological processes involved in cancer, including inflammation and immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle. Signaling pathways related to these biological processes, which include Mitogen-Activated Protein Kinases (MAPK), Nuclear Factor-κB (NF-ĸB), Nod-Like Receptor Pyrin domain containing 3 (NLRP3) inflammasome, Signal Transducer and Activator of Transcription 3 (STAT3) pathway, Warburg effect, Nuclear Factor Erythroid 2-related Factor 2 (NRF2), Hypoxia-Inducible Factor 1 alpha (HIF1α), mechanistic Target Of Rapamycin (mTOR), Ras, macroautophagy, cell cycle checkpoints, intrinsic and extrinsic apoptotic pathways, and senescence, are modulated by flavonoids in cancer and highlighted in this figure. Original figure made for this review using the Biorender software.
Figure 2
Figure 2
Flavonoids modulate inflammation and immunity pathways in cancer. Pro-inflammatory stimuli like TNF-α and Lipopolysaccharide (LPS) can bind to Tumor Necrosis Factor Receptor (TNFR) and TLR4 receptors, respectively, and activate the TAK1, which is mediated by TNFR-associated Death Domain (TRADD), TRAF2/5, and Receptor-Interacting Protein 1 (RIP) in response to TNF-α/TNFR signaling and Myd88 and TRAF6 in LPS-TLR4 signaling. TAK1 activates Mitogen-Activated Protein Kinases (MKKs) and I Kappa B Kinases (IKKs), leading to translocation of AP-1 and NF-κB to the nucleus. Flavonoids act mainly in inhibiting the nuclear translocation, expression, or phosphorylation of these transcription factors. The first signal for NLRP3 inflammasome activation is through NF-κB-mediated transcription of NLRP3. The second signal is mediated by Adenosine Triphosphate (ATP), Pathogen-Associated Molecular Patterns (PAMPs), Damage-Associated Molecular Patterns (DAMPs), and K+ efflux. When NLRP3 inflammasome is activated, caspase 1 cleaves pro IL-18 and pro-IL-1β in activated forms. Flavonoids act in this pathway mainly by inhibiting caspase 1 activity and reducing the NLRP3 expression. The TGR5-cAMP signaling pathway is activated by Genistein to lead to ubiquitination and degradation of NLRP3. Flavonoids also modulate the JAK2-STAT3 signaling, reducing inflammatory and EMT markers. Epi: Epigallocatechin, Kae: Kaempferol; Myr: Myricetin; Que: Quercetin; Api: Apigenin; Vit: Vitexin; Gen: Genistein; Dai: Daidzein; Lut: Luteolin; Nar: Naringenin; Tax: Taxifolin; Eri: Eriodictyol, Cya: Cyanidin. Original figure made for this review using the Biorender software.
Figure 3
Figure 3
Flavonoids modulate redox metabolism pathways in cancer. Flavonoids, in addition to functioning as free radical scavengers, also act on antioxidant system enzymes such as Superoxide Dismutases (SODs), Catalase (CAT), Cyclooxygenase-2 (COX-2), Glutathione (GSH), and Glutathione Disulfide (GSSG) in cancer. Additionally, some flavonoids can interact with NRF2, activating many systems responsible for the redox balance and cell detoxification such as Heme Oxygenase-1 (HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Isocitrate Dehydrogenase Dependent on NADP 1 (IDH1), and Malic Enzyme 1 (ME1). Hypoxia-Inducible Factor 1 (HIF1) has also been shown to be relocated, degraded, and inhibited by the action of flavonoids in cancer cells, thereby reducing receptors such as GLUT1 and glycolytic enzymes related to the Warburg effect such as PDK1, HK2, and PKM2, indirectly increasing the TCA cycle and not allowing the transformation of pyruvate into lactate. The inhibition of some cell growth proteins such as mTOR, AMPK, and AKT was also shown to be inhibited by flavonoids, affecting the c-Myc oncoprotein indirectly. Que: Quercetin; Epi: Epigallocatechin, Kae: Kaempferol; Myr: Myricetin; Que: Quercetin; Api: Apigenin; Gen: Genistein; Dai: Daidzein; Lut: Luteolin; Nar: Naringenin; Tax: Taxifolin; Eri: Eriodictyol; Vit: Vitexin. Original figure made for this review using the Biorender software.
Figure 4
Figure 4
Flavonoids modulate growth pathways in cancer. Most of the flavonoid compounds inhibit the AKT/mTOR and Ras/ERK signaling pathway, impairing especially the metabolism, proliferation, survival, growth, and angiogenesis in cancer cells. Flavonoids can inhibit the response of the tyrosine kinase receptors (RTKs), initially controlling the upstream signaling cascade. The signaling can bifurcate in two main pathways: the Ras/ERK and the AKT/mTOR signaling. The Ras/ERK signaling, which is important in tumor progression, can be both negatively and positively regulated by flavonoids. In the AKT/mTOR pathway, one of the primary stages of signaling is the conversion of PIP2 to PIP3. This conversion can be inhibited by some flavonoids by inhibiting their converter, PI3K, or by stimulating the reverse conversion of PIP3 to PIP2 through PTEN, known as a tumor suppressor. Although some compounds stimulate AKT, probably through a feedback loop, most flavonoid compounds can inhibit AKT, preventing the activation of mTOR and, consequently, its effectors. The compounds directly inhibit mTOR, in addition to inhibiting 4EBP1/2 and S6K1, proteins that control especially the translation initiation and ribosomal and mRNA biogenesis. The compounds also stimulate p53, which targets SESTRIN 1/2, to inhibit the AKT/mTOR pathway by stimulating AMPK. mTOR signaling also controls lipid synthesis and angiogenesis, which can be both inhibited by flavonoids. These inhibitory regulations direct the cells to inhibition of cancer progression. Epi: Epigallocatechin, Kae: Kaempferol; Myr: Myricetin; Que: Quercetin; Api: Apigenin; Gen: Genistein; Dai: Daidzein; Lut: Luteolin; Nar: Naringenin; Tax: Taxifolin; Eri: Eriodictyol; Vit: Vitexin. Original figure made for this review using the Biorender software.
Figure 5
Figure 5
Flavonoids modulate autophagy pathways in cancer. Macroautophagy begins by activation of ULK complex in the endoplasmic reticulum that leads to Beclin1 phosphorylation this permits the activation of PI3KC3 complex that converts PIP2 to PIP3 promoting an accumulation of phospholipid, this accumulation recruits Wipi proteins and some autophagy-related genes (Atg 5,12 and 16) for the formation of the single-layer pre-autophagosome (in blue), the autophagy receptor p62 interacts with the autophagy target and binds to active LC3-II forming a mature double membrane (in purple) that is fused with lysosomes that will digest the autophagosome content with cathepsin enzyme. Flavonoids can stimulate macroautophagy, through the increase in expression of Beclin1, p62, LC3-II, and some Atgs. Kae: Kaempferol, Myr: Myricetin, Que: Quercetin, Api: Apigenin, Gen: Genistein, Del: Delphinidin, Lut: Luteolin, Nar: Naringin, Epi: Epigallocatechin. Original figure made for this review using the Biorender software.
Figure 6
Figure 6
Flavonoids modulate apoptosis, cell cycle, DNA repair, and senescence pathways in cancer. Flavonoids can promote both down-regulation of anti-apoptotic proteins such as Bcl-2, Mcl-1, and Bcl-xL or upregulation of pro-apoptotic proteins as BAK, BAX, and BID. Besides that, flavonoids can also induce the conversion of pro-caspase 3 to activated Caspase 3. All these modulations lead to cancer cell death. Flavonoids also regulate proteins involved with the cell cycle, as p21, CDK1, CDK2, CKD4, and cyclins: D1, A, B, and E, culminating in cell cycle arrest. Proteins involved with DNA damage response as CHK1/2 also are modulated by flavonoids, inhibiting the ability of cancer cells to repair their DNA directing them to apoptosis. Quercetin can also regulate p16, a senescence marker. Epi: Epigallocatechin; Cat: Catechin; Kae: Kaempferol; Myr: Myricetin; Que: Quercetin; Api: Apigenin; Gen: Genistein; Dai: Daidzein; Cya: Cyanidin; Vit: Vitexin; Lut: Luteolin; Nar: Naringenin; Tax: Taxifolin; Eri: Eriodictyol. Original figure made for this review using the Biorender software.
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