Antiproliferative and pro-apoptotic activity of novel phenolic derivatives of resveratrol.
Gloriosaols A-C, isolated from Yucca gloriosa (Agavaceae), are novel phenolic compounds structurally related to resveratrol. In the present study, we show that gloriosaols possess antiproliferative and pro-apoptotic activity on tumor cells of different histogenetic origin and that their cell growth inhibition potential is higher than that of resveratrol. Despite the close similarities in their structure, gloriosaols A-C exhibited different antiproliferative potency, as the EC(50) ascending order is: gloriosaol C, gloriosaol A, gloriosaol B. Further mechanisms of gloriosaol C cytotoxicity were elucidated in detail in U937 cells, the most sensitive of the cell lines tested. The effect of gloriosaol C on cell growth turned out to be strongly dependent upon the concentration. Gloriosaol C doses lower than the EC(50) value (8 mu-icroM) blocked the cell cycle in G(0)/G(1), with a concurrent decrease in the number of cells in the G(2)/M phases of the cell cycle. At higher doses, this arrest overlaps with the occurrence of apoptosis and necrosis. In the 10-25 microM range of doses, gloriosaol C caused cell death mainly by apoptosis, as measured by hypodiploidia induction, phosphatidyl serine externalization and disruption of mitochondrial transmembrane potential. A switch in the mode of death from apoptosis to necrosis occurred at doses of gloriosaol C higher than 30 microM. Gloriosaol C was found to induce production of reactive species dose-dependently, but also to counteract their elevation in stressed cells. Thus, the different fate of cells, that is cell cycle arrest or cell death, in response to different doses of gloriosaol C might be related to the extent of induced oxidative stress.
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Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salerno, Italy.
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D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D016195:G2 Phase; D006801:Humans; D008564:Membrane Potentials; D009336:Necrosis; D018384:Oxidative Stress; D010636:Phenols / Q000737:chemistry; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
D016588:Anticarcinogenic Agents; D010636:Phenols; D017382:Reactive Oxygen Species; D013267:Stilbenes; C523756:gloriosaol C; D000077185:Resveratrol