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Gynecol Oncol. 2014 Jan;132(1):211-20. doi: 10.1016/j.ygyno.2013.11.013. Epub 2013 Nov 19.

YM155 sensitizes ovarian cancer cells to cisplatin inducing apoptosis and tumor regression.

Author information

1
Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
2
Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain; Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
3
Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, IDIBELL, Spain.
4
Department of Pathology, Hospital de Bellvitge, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, IDIBELL, Spain.
5
Department of Gynecology, Hospital de Bellvitge, Barcelona, Spain.
6
Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain. Electronic address: atortosa@ub.edu.
7
Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain. Electronic address: pgimenez@ub.edu.

Abstract

OBJECTIVE:

The objective of this study is to chemosensitize ovarian cancer (OVCa) cells to cisplatin (CDDP) using an inhibitor of Survivin, YM155. The efficacy of YM155 in combination with CDDP was determined in vitro, ex vivo and in vivo.

METHODS:

Human OVCa cell lines A2780p and their cisplatin-resistant derivative A2780cis, were treated with CDDP, YM155, and the combined treatment (YM155+CDDP), and cell viability, mRNA and protein expression levels, cell-cycle distribution, and DNA damage were then evaluated. Furthermore, the efficacy of YM155 combined with CDDP was further examined in established primary cell cultures and xenograft models.

RESULTS:

The combination of YM155 with CDDP induced G2/M cell cycle arrest and apoptosis, increased DNA damage, and decreased Survivin levels, especially in A2780cis CDDP-resistant cells. Additionally, YM155 in combination with CDDP sensitized primary cell cultures to CDDP. Studies in vivo showed how this combination significantly decreased the tumor size of OVCa xenografts.

CONCLUSIONS:

Our results demonstrate that in OVCa cells the expression of Survivin did not affect their sensitivity to YM155, suggesting that Survivin was not the only target of YM155. The combination of YM155 with CDDP could be a good option for therapy of CDDP-resistant OVCa, independently of p53 status.

KEYWORDS:

AnV; Annexin V; Apoptosis; CDDP; CI; Chemoresistance; Cisplatin; DSB; EOC; FBS; IAP; IP; LASC; MLPA; OVCa; Ovarian cancer; PBS; Propidium iodide; QVD; RT-PCR; Real time polymerase chain reaction; Survivin; YM155; ascites; caspase inhibitor Q-VD-Oph; cisplatin; combination index; double-strand breaks; epithelial ovarian cancer; fetal bovine serum; h; hour; inhibitor of apoptosis protein; multiplex ligation-dependent probe amplification; ovarian cancer; phosphate-buffered saline

PMID:
24262875
DOI:
10.1016/j.ygyno.2013.11.013
[Indexed for MEDLINE]

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