In vitro and in vivo antiproliferative effect of a combination of ultraviolet-A and alkoxy furocoumarins isolated from Umbelliferae medicinal plants, in melanoma cells

We examined the effects of six furocoumarins with alkoxy groups at the C-5 or C-8 position isolated from Umbelliferae medicinal Plants on cell proliferation, and their mechanisms of action against B16F10 Melanoma cells or in melanin-possessing hairless mice implanted with B16F10 cells, under UVA irradiation. Three furocoumarins with an alkoxy group at C-5, isoimperatorin (1), oxypeucedanin (2) and oxypeucedanin hydrate (3), showed antiproliferative activity and caused G2/M arrest at concentrations of 0.1-10.0 μm. Furthermore, three furocoumarins with an alkoxy group at C-8, imperatorin (4), heraclenin (5) and heraclenol (6), inhibited the proliferation of Melanoma cells and cell cycle at G2/M at concentrations of 0.1-1.0 μm. UVA plus 1, 2, 3, 4 and 6 reduced tumor growth and final tumor weight in B16F10-bearing mice at a dose of 0.3, 0.5 or 1.0 mg kg(-1) (intraperitoneal injection). UVA plus 1, 3 and 6 increased Chk1 phosphorylation and reduced cdc2 (Thr 161) phosphorylation in Melanoma cells. We suggest that the antitumor actions of UVA plus furocoumarins with an alkoxy group at C-5 or C-8 were due to G2/M arrest of the cell cycle by an increase in phosphor-Chk1 and decrease in phospho-cdc2.