Original ContributionWithaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP
Section snippets
Cells and materials
Caki, Huh7, SK-Hep1, and Hep3B cells were obtained from the American Type Culture Collection (Rockville, MD, USA). Primary culture of human renal glomerular mesangial cells (Cryo NHMC) and their corresponding growth medium (CC-3146 MsGM) were purchased from Clonetics (San Diego, CA, USA). The culture medium used throughout these experiments was Dulbecco's modified Eagle's medium, containing 10% FBS, 20 mM Hepes buffer, and 100 μg/ml gentamicin. Wit A (Sigma) was directly added to cell cultures
Wit A sensitizes cancer cells to TRAIL-mediated apoptosis
In an attempt to search for novel strategies to overcome TRAIL resistance in cancer cells, we investigated the effect of a combined treatment with Wit A and TRAIL in a human renal carcinoma cell line, Caki cells. Caki cells were treated with 1.2 μM Wit A alone, 100 ng/ml TRAIL alone, or the combination of Wit A and TRAIL for 24 h. Cotreatment of Caki cells with Wit A and TRAIL resulted in a markedly increased accumulation of sub-G1-phase cells and a typical ladder pattern of internucleosomal
Discussion
TRAIL is considered a highly promising candidate as an anti-cancer drug, because it has been shown to induce apoptosis specifically in malignant or transformed cells without any cytotoxicity toward a variety of normal cells [26], [27], [28]. However, considerable numbers of cancer cells are resistant to treatment with TRAIL, and this resistance may be caused by deregulated expression of antiapoptotic molecules [29], [30], [31], [32]. Therefore, novel therapeutic strategies are necessary to
Acknowledgments
This work was supported by the Korea Science and Engineering Foundation through the MRC at Keimyung University (R13-2002-028-03001-0) and BAERI-M20708630003-07B0863-00310 and Korea Research Foundation Grant KRF-2005-070-C00100.
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These authors contributed equally to this work.