Downregulation of XIAP expression in ovarian cancer cells induces cell death in vitro and in vivo.
A hallmark of cancer cells is an ability to evade apoptosis. Overexpression and/or activating mutations of prosurvival molecules such as the X-linked inhibitor of apoptosis (XIAP) contribute to this inappropriate cell survival. Our objectives were to investigate the effects of downregulation of XIAP in ovarian cancer cells in vitro and in vivo using the clinical candidate antisense oligonucleotide against XIAP, AEG35156 (AS XIAP). Three ovarian cancer cell lines were transfected with AS XIAP in vitro, and the effects on cell survival were assessed. Downregulation of XIAP resulted in significant apoptosis. To investigate the in vivo efficacy of AS XIAP, CD-1 nude mice were xenografted intraperitoneally with A2780-cp cells, treated with intraperitoneal AS XIAP and evaluated for survival time and tumor histology. Mice treated with 10 mg/kg/day AS XIAP showed a significant improvement in survival time compared to animals treated with control oligonucleotides. Histological analysis of the tumors showed significantly fewer viable cells in the AS XIAP-treated tumors. Downregulation of XIAP expression in ovarian cancer cells resulted in apoptosis in vitro and a prolonged survival time of ovarian cancer-bearing mice, which indicate that XIAP may be a valuable therapeutic target in ovarian cancers, and supports the ongoing clinical investigation of AEG35156.
Shaw
Tanya J
TJ
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Lacasse
Eric C
EC
Durkin
Jon P
JP
Vanderhyden
Barbara C
BC
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D017931:DNA Primers; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism* / Q000502:physiology
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human