Tubulin inhibitor AEZS 112 inhibits the growth of experimental human ovarian and endometrial cancers irrespective of caspase inhibition.
AEZS 112 is an orally active small molecule anticancer drug which inhibits the polymerization of tubulin at low micromolar concentrations. The current study investigates the anti-tumor effect and the mechanism of action of AEZS 112 in in vitro models of human ovarian and endometrial cancers. Four human ovarian and 2 endometrial cancer cell lines were incubated with increasing concentrations of AEZS 112 with and without multi-caspase inhibitor zVAD-FMK for 72 hours. Cytotoxic effects of AEZS 112 were analyzed using crystal violet staining, FACS analysis of DNA content as well as Annexin V/propidium iodide-double staining. AEZS 112 displayed anti-tumor activity in all six cell lines. The EC50 determined after 72-h incubation for Ishikawa and HEC 1A was 0.0312 and 0.125 microm, respectively. The EC50 was 5 microm for SKOV 3 cells, 1 microm for 0.5 microm for OAW 42 cells, 0.125 microm for OvW 1 cells and 0.0312 microm for PA 1 cells. Cytotoxic effects of AEZS 112 could not be abrogated by caspase inhibition with pan-caspase inhibitor zVAD-fmk. Annexin V/propidium iodide-double staining after treatment with AEZS 112 was indicative of necrosis-like cell death. AEZS 112 dose-dependently increased non-vital hypodiploid cells and the cytotoxic effect was least pronounced in G2 phase of the cell cycle, indicating cell death during mitosis, as determined by FACS analysis. The orally active small molecule tubulin inhibitor AEZS 112 showed anti-tumor activity in human ovarian and endometrial cancer cell lines at low micromolar concentrations, which could not be abrogated by caspase inhibition and is therefore a good candidate for in vivo studies in these tumors.
Engel
Jörg B
JB
Universitätsfrauenklinik Würzburg, D-97080 Würzburg, Germany. joergbengel@hotmail.com
Schönhals
Tanja
T
Weidler
Claudia
C
Häusler
Sebastian
S
Krockenberger
Mathias
M
Rieger
Lorenz
L
Dietl
Johannes
J
Wischhusen
Jörg
J
Honig
Arnd
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D050257:Tubulin Modulators; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011065:Poly(ADP-ribose) Polymerases