Autors: Pan MH, Chen WJ, Lin-Shiau SY, Ho CT and Lin JK

Research Institute: Institutes of Biochemistry, College of Medicine, National Taiwan University, Taipei (Taiwan)

Publication: Carcinogenesis. 2002 October;23(10):1677-84

Studies have shown that citrus flavonoids have anti-carcinogenic and anti-tumor activities. These flavonoids seem to mainly interact with protein tyrosine kinases (an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein) and cyclooxygenase (an enzyme that is responsible for formation of biological mediators called prostanoids). The five methoxyl groups of tangeretin make it a more potent phytochemical than flavonoids with free hydroxyl groups. Tangeretin can be found in the peel of citrus fruits, where it probably acts as an antifungal agent. The peel of Dancy tangerins contains 5x higher levels of tangeretin than oranges. Previous studies have shown that tangeretin enhances gap junctional intracellular communication and inhibits cancer cell growth. This article describes the cell cycle regulation by proteins in eukaryotic cells. The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase and M phase. Cyclins are proteins involved in the progression of cells through these phases. A cyclin forms a complex with its cyclin-dependent kinase (Cdk), thereby activating its protein kinase function. Before these kinases can become active they need to be phosphorylated by other kinases: Cdk-activating kinases (CAK). They can become deactivated by another phosphorylation or by binding to Cdk inhibitory units (CKI). The retinoblastoma protein (Rb), a tumor suppressor protein, is a critical target protein for Cdks. One important function of Rb is the inhibition of the cell cycle. Rb can prevent mutated cells from dividing and becoming cancerous. P53 is transcriptional regulator that regulates the cell cycle and hence functions as a tumor suppressor, by inducing cell growth arrest and apoptosis. The proteins p27 and p21 are cell cycle inhibitors.

The aim of this study was to determine the effects of flavonoids (tangeretin, apigenin, luteolin, quercetin, rutin, kaempferol, nobiletin and myricetin) on the growth of colon cancer cells. They measured cyclin levels, p53 protein levels, phosphorylation state of Rb and the activities of some kinases. They found that mainly tangeretin, but also luteolin and nobiletin inhibited cell growth of the colon cancer cells. Tangeretin block the cell cycle in the G0/G1 phase, decreased the phosphorylation of Rb and slightly reduced levels of Cyclins (A, D1 and E). Tangeretin further increased the production of p53, p27 and p21. The increase in the p21 and p27 levels was dependent on p53 activity. The results indicate that tangeretin inhibits cell growth of colon cancer cells by increasing CKI levels (p21, p27 and p53) and decreasing the activity of some Cdks.