Phloretin is a dihydrochalcone flavonoid that inhibits yeast-derived GLUT1 and erythrocyte GLUT1 with IC50 values of 49μM and 61μM, respectively[1]. Phloretin displays potent antioxidant activity in peroxynitrite scavenging and the inhibition of lipid peroxidation, modulates Ca2+ levels and down-regulates the secretion of IL-2 of normal human lymphocytes, and counteracts advanced glycation end product formation[2]. Phloretin can penetrate the skin and has been widely used in dermatological research to prevent excessive skin pigmentation and skin damage[3].
In vitro, Phloretin treatment for 48 hours significantly inhibited the viability of HCT-116, SW-480, and IEC-6 cells, with IC50 values of 152.43µM, 127.50µM, and 412.56µM, respectively[4]. Treatment with 200µM Phloretin for 48 hours induced morphological changes in U87 and U251 cells, caused cell cycle arrest and accumulation of reactive oxygen species (ROS), inhibited the PI3K/Akt/mTOR signaling pathway, and increased the expression of PTEN[5]. Treatment with 75µg/ml Phloretin for 24 hours elicited apoptosis in A549 and Calu-1 cells, enhanced the expression of cleaved-caspase-3 and caspase-9, and decreased the levels of MMP-2 and MMP-9[6].
In vivo, Phloretin treatment via intraperitoneal injection at a dose of 20mg/kg, twice a week for 12 weeks, reduced the body weight and fat weight of obese mice on a high-fat diet (HFD), and alleviated hepatocyte steatosis[7]. Daily intraperitoneal injection of Phloretin (20mg/kg/day) for 7 days alleviated acute lung injury induced by lipopolysaccharide (LPS) in mice, inhibited neutrophil infiltration into lung tissue, and reduced the levels of IL-6 and TNF-α in serum and bronchoalveolar lavage fluid[8].
References:
[1] KASAHARA T, KASAHARA M. Expression of the rat GLUT1 glucose transporter in the yeast Saccharomyces cerevisiae[J]. Biochemical Journal, 1996, 315(1): 177-182.
[2] Behzad S, Sureda A, Barreca D, et al. Health effects of phloretin: from chemistry to medicine[J]. Phytochemistry reviews, 2017, 16(3): 527-533.
[3] Casarini T P A, Frank L A, Pohlmann A R, et al. Dermatological applications of the flavonoid phloretin[J]. European Journal of Pharmacology, 2020, 889: 173593.
[4] Kapoor S, Padwad Y S. Phloretin induces G2/M arrest and apoptosis by suppressing the β-catenin signaling pathway in colorectal carcinoma cells[J]. Apoptosis, 2023, 28(5): 810-829.
[5] Liu Y, Fan C, Pu L, et al. Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species[J]. Journal of Neuro-oncology, 2016, 128(2): 217-223.
[6] Ma L, Wang R, Nan Y, et al. Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases[J]. International Journal of Oncology, 2015, 48(2): 843-853.
[7] Liou C J, Wu S J, Shen S C, et al. Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice[J]. Cell & Bioscience, 2020, 10(1): 114.
[8] Huang W C, Lai C L, Liang Y T, et al. Phloretin attenuates LPS-induced acute lung injury in mice via modulation of the NF-κB and MAPK pathways[J]. International immunopharmacology, 2016, 40: 98-105.