Citrus peel polymethoxyflavones, sudachitin and nobiletin, induce distinct cellular responses in human keratinocyte HaCaT cells

A variety of polyphenols have been isolated from plants, and their biological activities have been examined. Sudachitin (5,7,4′-trihydroxy-6,8,3′-trimethoxyflavone) is a polymethoxyflavone that is isolated from the peel of Citrus sudachi. Although we previously reported that sudachitin possesses an anti-inflammatory activity, its other biological activities are not yet understood. In this study, we report a novel biological activity of sudachitin, which selectively induced apoptosis in human keratinocyte HaCaT cells. Another polymethoxyflavone, nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone), promoted autophagy but not apoptosis in HaCaT cells. On the other hand, 3′-demethoxysudachitin (5,7,4′-trihydroxy-6,8-dimethoxyflavone) failed to induce apoptosis and autophagy. These results show that three polymethoxyflavones have different effects on apoptosis and autophagy in HaCaT cells. Understanding the structure and biological activity of polymethoxyflavones may lead to the discovery of potential candidates for cancer drug development without significant toxic side effects. Abbreviations: ROS: reactive oxygen species; DMSO: dimethyl sulfoxide; MTT: 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; PARP: poly(ADP-ribose) polymerase; PI: propidium iodide; MAPK: mitogen-activated protein kinase.