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01-03-2011 | Gynecologic Oncology

Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers

Authors: Jörg B. Engel, Tanja Schönhals, Sebastian Häusler, Mathias Krockenberger, Melanie Schmidt, Evi Horn, Frank Köster, Johannes Dietl, Jörg Wischhusen, Arnd Honig

Published in: Archives of Gynecology and Obstetrics | Issue 3/2011

Abstract

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 24 h were >40 μM, IC₅₀ values after 72 h decreased to 10 μM in OAW42 and 25 μM in PA-1 and 30 μm in SKOV3 cells. In platinum resistant A2780cis cells perifosine showed good antiproliferative activity (IC₅₀ = 3 μm). 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.

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Title: Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers
Authors: Jörg B. Engel
Tanja Schönhals
Sebastian Häusler
Mathias Krockenberger
Melanie Schmidt
Evi Horn
Frank Köster
Johannes Dietl
Jörg Wischhusen
Arnd Honig
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Archives of Gynecology and Obstetrics / Issue 3/2011
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI: https://doi.org/10.1007/s00404-010-1457-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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