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Phloretin
Phloretin is a naturally occurring molecule found in plants that belong to the Rosacceae family, such as apples and pears. It is an active phenol with antioxidant activity. Phloretin is also a reversible biological inhibitor of many molecules such as urea, glucose and the gene PI3K/AKT. Activation of PI3K/AKT gene has been linked to progression of glioblastoma, a tumour of the central nervous system. A key role of Phloretin is the activation of apoptosis (cell death) pathways by inhibiting Protein Kinase C. Phloretin can be used as a therapeutic mechanism in tumours due to its ability to decrease cell proliferation. Phloretin also regulates the flow of ions into cell membranes through ion channels, by increasing flow of cations into the cell and decreasing flow of anions into the cell.

Role in Tumour Cells
Phloretin plays a therapeutic role in glioblastoma by activating apoptosis of the tumour cells. A decrease in PTEN activity and an increase in PI3K/AKT activity are responsible for the development of the cancer. Phloretin is known to increase the tumour suppressor gene PTEN, which inhibits cyclin-CDK genes; cyclin CDKs increase tumour cell proliferation. As CDKs are decreased in the cell, the transitions in the cell cycle are halted, resulting in less tumour cell production. PI3K/AKT genes are responsible for the progression of glioblastoma; Phloretin can combat this because it is known to inhibit PI3K/AKT gene activation.

Effects on Transport
Phloretin is a weak acid that affects the movement of cations and anions across membranes that have ion channels. Phloretin stimulates the movement of positive ions into the cell and inhibits the movement of negative ions into the cell. There are two forms of phloretin, uncharged and charged. Uncharged Phloretin decreases the transport of chloride, acetamide, and glucose across membranes. Thus, its binding action is non-specific and it is able to inhibit various biological molecules.

Glucose Transport
Both Phloretin and its glucoside phlorizin decrease the transport of glucose into the brain, intestine, kidneys and red blood cells. It was observed that kidneys on a Phlorizin infusion had a better ability to inhibit glucose transport than phloretin infused kidneys. This suggests that phloretin partially inhibits glucose transport while phlorizin competitively inhibits glucose transport. Phloretin binds closely to the sugar binding sites allowing inhibition of glucose transport, while Phlorizin directly binds to the sugar binding sites on the cell surface. However, in the absence of Phlorizin, glucose absorption quickly recovered. Whereas with phloretin, glucose absorption recovered slowly.

Glucose Transport in Red Blood Cells
In red blood cells absorbtion of phloretin is rapid and halts glucose transport. Once the phloretin concentration decreases, the cells slowly start to transport glucose again. However, with phlorizin, the cells quickly restore glucose transport once it is removed. Phloretin is a more potent inhibitor of glucose transport in red blood cells than phlorizin. Whereas, phlorizin is a more potent inhibitor of glucose transport in the kidney and intestine.

Role in Cardiovascular System
Like other flavonoids, phloretin stimulates vasodilation in blood vessels. Phloretin is able to exert it effects directly on the smooth muscle whether or not the endothelium is intact.

Phloretin mainly binds to red blood cells via hemoglobin. Once the hemoglobin component is removed, phloretin loses its ability to rapidly bind to red blood cells. This suggests that phloretin permeates the red cell membrane to access hemoglobin. As the hemoglobin concentration increases, phloretin is still able to bind to the molecules suggesting it does not get saturated.