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Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II

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Abstract

F14512, an epipodophyllotoxin derivative equipped with a spermine moiety, is selectively taken up by the polyamine transport system over-active in tumor cells. F14512 was identified as a selective anticancer agent with a broad spectrum of antitumor activities and is currently undergoing phase I clinical trial in onco-hematology. However, the mechanism by which F14512 exerts its selective effects on neoplastic cells remains poorly understood. In this study, using mainly P388 leukemia cells, we showed that activation of the DNA damage response by F14512 did not induce immediate apoptosis but resulted in an early growth arrest. F14512-induced G2 arrest was accompanied by the appearance of a senescence-like phenotype (characterized by an increased β-galactosidase staining) with up-regulation of the cyclin-dependent kinase inhibitor p16, and cyclin D1. The early senescence-based cell cycle block was characterized by a marked increase of the level of the IAP protein survivin, but not cIAP2, in P388 cells as well as in three other leukemia and melanoma cell types. The Thr(34)-phosphorylated form of survivin was observed within 4 h after F14512 exposure. Inhibition of survivin by siRNA resulted in a switch from senescence-like growth arrest to apoptosis. Compared with the parental drug etoposide, F14512-induced DNA damage signaling pathway resulted in greater senescence like-growth arrest and delayed apoptosis. Collectively, our data show that senescence arrest and subsequent apoptosis are powerful mechanisms mediating the chemotherapeutic effects of F14512 and identify survivin as the molecular determinant responsible for a qualitative shift in cell fate from senescence to apoptosis upon treatment with F14512.

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Abbreviations

IAP:

Inhibitor of apoptosis

DSBs:

Double-strand breaks

RT:

Room temperature

z.VAD.fmk:

Benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone

PTS:

Polyamine transport system

NSCLC:

Non small cell lung carcinoma

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Acknowledgments

This work received a financial support from INSERM, UNIVERSITE DE LILLE II, the Ligue Contre le Cancer (Comité de l’Aisne) and the Institut de Recherche Pierre Fabre (to PM). JK received a fellowship from the ARC. The authors acknowledge the Institut de Recherche Pierre Fabre (IRPF) for providing F96982 and F14512 and for useful discussions with the CROE research group.

Conflict of interest

Christian Bailly is employed by Pierre Fabre Médicament which provided a support to this work. The products F96982 and F14512 were synthesized by Pierre Fabre Médicament.

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Authors and Affiliations

  1. UMR837 Equipe 4 Inserm and Faculté de Médecine, Université de Lille II, 1 Place Verdun, 59045, Lille Cedex, France

    Caroline Ballot, Manel Jendoubi, Jérome Kluza, Aurélie Jonneaux, William Laine, Pierre Formstecher & Philippe Marchetti

  2. Institut de Recherche Pierre Fabre, Centre de Recherche et de Développement, 3 Avenue Hubert Curien BP13562, 31035, Toulouse Cedex, France

    Christian Bailly

  3. Centre de Bio-Pathologie, Plate-forme de Biothérapie, et Banque de Tissus, CHRU Lille, Lille, France

    Philippe Marchetti

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  1. Caroline Ballot
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  2. Manel Jendoubi
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Correspondence to Philippe Marchetti.

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Ballot, C., Jendoubi, M., Kluza, J. et al. Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II. Apoptosis 17, 364–376 (2012). https://doi.org/10.1007/s10495-011-0681-2

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