Table 1.

Anti-inflammatory and anti-cancer activities of phloretin.

Type	Experimental Model	Dose/Concentration	Mechanism of Action	Ref.
Anti-inflammatory	HEK293 cells engineered to either overexpress or deficient in hTLR2	10 or 20 µM	Inhibits the heterodimerization of TLR2/1; reduced the secretion of TNF-α and IL-8	[33]
	Specific pathogen-free male BALB/c mice (6–8 weeks, 22–24 g)	20 mg/kg	Suppressed the mucins secretion, inflammatory cell infiltration and cytokine release in mouse lungs induced by cigarette smoke (CS)	[27]
	OVA-challenged asthmatic mice	5, 10, or 20 mg/kg	Decreased hyperresponsiveness, inflammation, and oxidative responses; reduced ROS, and cytokines production	[26]
	LPS-induced acute lung injury in mice	5 or 20 mg/kg	Suppressed LPS-induced neutrophil infiltration, and reduce the levels of IL-6 and TNF-α in serum and bronchoalveolar lavage fluid; blockade of the NF-κB and MAPK pathways	[34]
	A549 cells	3–100 μM	Inhibited proinflammatory cytokine, COX-2, and ICAM-1 expression; blocked NF-κB and MAPK signaling pathways.	[35]
	TNF-α-stimulated HaCaT human keratinocytes	10, 30, or 100 μM	Decreased the production of IL-6, IL-8, and CCL5; inhibited NF-κB nuclear translocation; suppressed phosphorylation of Akt and MAPK signal.	[36]
	Human THP-1 monocytes	1, 10, or 30 μg/mL	Reduced TNF-α, IL-6 and COX-2 expression	[37]
	Rat basophilic leukemia RBL-2H3 cells	12.5, 25, or 50 μM	Attenuated ROS production, phosphorylation of Akt, ERK1/2, p38 MAP kinase, and JNK	[38]
	LPS-stimulated murine RAW264.7 macrophages	3, 10, 30, or 100 μM	Reduced the levels of NO, PGE2, IL-6, TNF-α, iNOS and COX-2; suppressed nuclear translocation of NF-κB subunit p65 proteins, and decreased phosphorylation of MAPK pathways	[16]
Anti-cancer	Gastric cancer (AGS) cells	IC50 8 μM	Arrested the cell cycle in G2/M phase and decreased the expression of p-JNK and p-p38 MAP kinase	[39]
	Esophageal cancer EC-109 cell lines	60 µg/mL	Apoptosis increased to 225.6 ± 16.0%; increased p53 activity; increased the level of Bax and declined Bcl-2 levels	[40]
	Non-small cell lung cancer (NSCLC): A549, Calu-1, H838 and H520 cells	25, 50 or 75 μg/mL	Suppressed the expression of Bcl-2; increased the protein expression of cleaved-caspase-3 and -9, and deregulated the expression of MMP-2 and -9 on gene and protein levels	[41]
	Human erythroid leukemia K-562 cells	20 μM	Increased the efficacy of HSP70 penetration; increases anti-tumor activity of HSP70 with phloretin combination	[42]
	A549 human lung cancer cell line, Bel 7402 liver cancer cell line, HepG2 human ileocecal cancer cell line, and HT-29 human colon cancer cell line	0–150 mg/mL	Significant positive anti-cancer activities against several human cancer cell lines, IC50: A549 (27 μg/mL), BEL7402 (37 μg/mL, HepG2 (37 μg/mL), HT29 (33 μg/mL)	[43]
	HepG2-xenografted tumor	10 mg/kg phloretin or +1 mg/kg paclitaxel	Reduced tumor growth more than fivefold in the phloretin and paclitaxel-treated mice compared to the paclitaxel only treated mice	[15]