1. Synthetic Analogue of Rocaglaol Displays a Potent and Selective Cytotoxicity in Cancer Cells: Involvement of Apoptosis Inducing Factor and Caspase-12.
- Author
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Frédéric Thuaud, Yohann Bernard, Gülen Türkeri, Ronan Dirr, Geneviève Aubert, Thierry Cresteil, Aurélie Baguet, Catherine Tomasetto, Yuri Svitkin, Nahum Sonenberg, Canan G. Nebigil, and Laurent Désaubry
- Subjects
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BENZOFURAN , *CELL-mediated cytotoxicity , *APOPTOSIS , *PROTEOLYTIC enzymes , *ANTINEOPLASTIC agents , *CANCER cell proliferation , *DRUG dosage , *ORGANIC synthesis - Abstract
Flavaglines constitute a family of natural anticancer compounds. We present here 3(FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC50≈1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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