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Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis

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Abstract

Ovarian cancer is the leading cause of death from gynecological cancer. The anti-apoptotic protein Bcl-xL is frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that Bcl-xL cooperates with another anti-apoptotic protein, Mcl-1, to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition induces massive cell death. Here, we examined the interest of ABT-737, a potent BH3-mimetic molecule targeting Bcl-xL, both alone and in combination with Mcl-1 modulators, in ovarian cancer cell lines. As a single agent, ABT-737 was ineffective at promoting cell death in the four cell lines we tested in vitro. However, the specific inhibition of Mcl-1 by siRNA dramatically increased the sensitivity of chemoresistant cells to ABT-737. Platinum compounds also sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Furthermore, we demonstrated that Noxa accumulation was involved in apoptosis occurring in response to the combination of ABT-737 and platinum compounds, since cells were protected from apoptosis by its silencing. Moreover, the combination was also highly cytotoxic ex vivo in sliced SKOV3 tumor nodes. However we observed in these slices a strong basal expression of Noxa and apoptotic cell death in response to ABT-737 alone. Therefore, we have revealed that the modulation of the Mcl-1/Noxa axis by platinum compounds results in a strong sensitization of chemoresistant ovarian carcinoma cells to ABT-737, which could constitute a promising therapeutic in these cancers.

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Abbreviations

CA:

Carboplatin

CDDP:

Cisplatin (cis-diammino-dichloro-platinum(II))

CHX:

Cycloheximide

DAPI:

4′,6-diamidino-2-phenylindole

PARP:

Poly (ADP-ribosyl) polymerase

PI:

Propidium iodide

HA14-1:

Ethyl [2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate

HES:

Hematoxylin eosin safran

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Acknowledgments

We acknowledge Edwige Lemoisson, Marie-Hélène Louis (BioTICLA Unit) and Maryline Duval (Flow cytometry accommodation, SF 4206 ICORE, University of Caen) for their helpful technical support and ABBOTT Laboratories for providing us with ABT-737. We also acknowledge AngloScribe society for English language editing. This work was supported by the “Ligue Contre le Cancer” (Calvados and Manche’s committee), the “Conseil Régional de Basse–Normandie” and the French State. KS was the recipient of a doctoral fellowship from the “Ligue Contre le Cancer” (Calvados’s Committee). Acquisition of the xCELLigence real-time activity measurement system has been supported by European Community (FEDER) and Comprehensive Cancer Center F. Baclesse.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Unité “Biologie et Thérapies Innovantes des Cancers Localement Agressifs” (EA 4656, Université de Caen Basse-Normandie et SF 4206 ICORE), Centre de Lutte Contre le Cancer François Baclesse, 3 Avenue du Général Harris, BP 5026, 14076, Caen Cedex 05, France

    Karin Simonin, Monique N’Diaye, Stéphanie Lheureux, Claire Loussouarn, Soizic Dutoit, Mélanie Briand, Florence Giffard, Emilie Brotin, Cécile Blanc-Fournier & Laurent Poulain

  2. Service de recherche clinique, Centre de Lutte Contre le Cancer François Baclesse, 3 Avenue du Général Harris, BP 5026, 14076, Caen Cedex 05, France

    Stéphanie Lheureux

  3. Laboratoire d’Anatomie Pathologique, Centre de Lutte Contre le Cancer François Baclesse, 3 Avenue du Général Harris, BP 5026, 14076, Caen Cedex 05, France

    Cécile Blanc-Fournier

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  1. Karin Simonin
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  2. Monique N’Diaye
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  3. Stéphanie Lheureux
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  9. Cécile Blanc-Fournier
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  10. Laurent Poulain
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Correspondence to Monique N’Diaye or Laurent Poulain.

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Karin Simonin and Monique N’Diaye contributed equally to this work.

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Simonin, K., N’Diaye, M., Lheureux, S. et al. Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis. Apoptosis 18, 492–508 (2013). https://doi.org/10.1007/s10495-012-0799-x

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