caa a22 4500 445306963 CHVBK 20180317142616.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s00404-010-1457-6 doi (NATIONALLICENCE)springer-10.1007/s00404-010-1457-6 Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers [Elektronische Daten] [Jörg Engel, Tanja Schönhals, Sebastian Häusler, Mathias Krockenberger, Melanie Schmidt, Evi Horn, Frank Köster, Johannes Dietl, Jörg Wischhusen, Arnd Honig] Purpose: We analyzed the anti-tumor effect and the mechanism of action of perifosine, an orally active alkylphospholipid AKT inhibitor using in vitro models of human ovarian cancer. Methods: Ovarian cancer cells OAW42, PA-1, SKOV3, and A2780 as well as platinum resistant A2780cis cells were incubated with increasing concentrations of perifosine, with and without multi-caspase inhibitor zVAD-FMK. The effect of a combined treatment with cisplatin and perifosine was investigated in OAW42, SKOV3, A2780 and A2780cis cells. Cytotoxic effects of perifosine were analyzed using crystal violet staining, FACS analysis of DNA content as well as Annexin V/propidium iodide-double staining. The effect of perifosine on AKT phosphorylation was determined by Western blotting. Results: Perifosine displayed anti-tumor activity in all five cell lines, which increased time-dependently. While IC50 values at 24h were >40μM, IC50 values after 72h decreased to 10μM in OAW42 and 25μM in PA-1 and 30μm in SKOV3 cells. In platinum resistant A2780cis cells perifosine showed good antiproliferative activity (IC50=3μm). At adequate doses, perifosine increased cytotoxic effects of cisplatin in OAW42, A2780 and A2780cis cell. Anti-tumor activity of perifosine was not confined to a specific phase of the cell cycle and could not be decreased by the pan-caspase inhibitor zVAD-FMK. AnnexinV/propidium iodide-double staining after treatment with perifosine was not indicative of classical apoptosis. AKT phosphorylation was dose-dependently inhibited by perifosine. Conclusions: Perifosine showed substantial cytotoxic effects in various in vitro models of ovarian cancer. Since anti-tumor effects were not confined to platinum-sensitive cells perifosine seems to be a good candidate for clinical studies in patients especially with platinum resistant ovarian cancer. Springer-Verlag, 2010 Ovarian cancer nationallicence AKT nationallicence Perifosine nationallicence Small molecules nationallicence Platinum resistance nationallicence PCD : Programmed cell death nationallicence zVAD-FMK : Broad spectrum caspase inhibitor benzyloxycarbonyl-val-ala-asp(OMe)-fluoromethylketone nationallicence FACS : Fluorescence activated cell sorting nationallicence Engel Jörg Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Schönhals Tanja Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Häusler Sebastian Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Krockenberger Mathias Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Schmidt Melanie Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Horn Evi Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Köster Frank Universitätsfrauenklinik Lübeck, Universität Schleswig-Holstein, Campus Lübeck, Lübeck, Germany aut Dietl Johannes Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Wischhusen Jörg Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Honig Arnd Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut Archives of Gynecology and Obstetrics Springer-Verlag 283/3(2011-03-01), 603-610 0932-0067 283:3<603 2011 283 404 https://doi.org/10.1007/s00404-010-1457-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00404-010-1457-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Engel Jörg Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Schönhals Tanja Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Häusler Sebastian Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Krockenberger Mathias Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Schmidt Melanie Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Horn Evi Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Köster Frank Universitätsfrauenklinik Lübeck, Universität Schleswig-Holstein, Campus Lübeck, Lübeck, Germany aut NATIONALLICENCE 700 1- Dietl Johannes Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Wischhusen Jörg Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 700 1- Honig Arnd Universitätsfrauenklinik Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany aut NATIONALLICENCE 773 0- Archives of Gynecology and Obstetrics Springer-Verlag 283/3(2011-03-01), 603-610 0932-0067 283:3<603 2011 283 404 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer