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Vorinostat and Mithramycin A in combination therapy as an interesting strategy for the treatment of Sézary T lymphoma: a transcriptomic approach

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Abstract

SAHA (vorinostat) is a histone deacetylase inhibitor approved by the USA Food and Drug Administration (FDA) for treating advanced refractory cutaneous T cell lymphomas. As SAHA alters the expression of many genes under control of the Sp1 transcription factor, we examined the effect of its association with the FDA-approved anticancer antibiotic Mithramycin A (MTR, plicamycin), a competitive inhibitor of Sp1 binding to DNA. Sézary syndrome (SS) cells, expanded ex vivo from peripheral blood mononuclear cells of 4 patients, were tested for their sensitivity to the drugs regarding cytotoxicity and differential responsive gene expression. Multivariate statistical methods were used to identify genes whose expression is altered by SAHA, MTR, and the synergist effect of the two drugs. MTR, like SAHA, induced the apoptosis of SS cells, while the two drugs in combination showed clear synergy or potentiation. Expression data stressed a likely important role of additive or synergistic epigenetic modifications in the combined effect of the two drugs, while direct inhibition of Sp1-dependent transcription seemed to have only limited impact. Ontological analysis of modified gene expression suggested that the two drugs, either independently or synergistically, counteracted many intertwined pro-survival pathways deregulated in SS cells, resistance of these tumors to intrinsic and extrinsic apoptosis, abnormal adhesion migration, and invasive properties, as well as immunosuppressive behavior. Our findings provide preliminary clues on the individual and combined effects of SAHA and MTR in SS cells and highlight a potential therapeutic interest of this novel pair of drugs for treatment of SS patients.

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Abbreviations

SAHA:

Suberoylanilide hydroxamic acid

MTR:

Mithramycin A

CI:

Combination index

CTCL:

Cutaneous T cell lymphomas

FC:

Fold change

FDR:

False discovery rate

GO:

Gene ontology

Sp1:

Specificity protein 1

SS:

Sézary syndrome

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the French National Research Agency (ANR-08-SYSC-003 CALAMAR). We thank Ms. L. Borg for expert supervision of Marseille Luminy cell culture facilities, Dr. J. Imbert (TAGC), Dr. A. Bergon, and Mr. Nicolas Fernandez (transcriptomic and Genomic Marseille-Luminy TGML/TAGC platform) for their helpful advice for the preparation of the manuscript.

Availability of supporting data

The microarray data included in the paper have been deposited under embargo in GEO to be released upon acceptance of the paper for publication at: (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=glypyyownjmtnmp&acc=GSE64119).

Author information

Author notes

  1. R. Ragheb and G. Venton contributed equally to this work.

Authors and Affiliations

  1. Aix Marseille Université, INSERM UMR_S 1090, Technological Advances for Genomics and Clinics, 13288, Marseille-Luminy, France

    R. Ragheb, G. Venton, R. Chelbi, P. Rihet, B. Loriod, B. Kahn-Perlès & Régis T. Costello

  2. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Conception, Service d’Hématologie et de Thérapie Cellulaire, 13005, Marseille, France

    G. Venton, V. Ivanov, C. Mercier & Régis T. Costello

  3. Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Service de Dermatologie, 13915, Marseille, France

    N. Bonnet

  4. Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Laboratoire d’Hématologie, 13915, Marseille, France

    T. Le Treut

  5. Assistance Publique Hôpitaux de Marseille, Hôpital La Conception, Service d’Hémaphérèse, 13005, Marseille, France

    P. Poulin

  6. Assistance Publique des Hôpitaux de Marseille, Hôpital Nord, Laboratoire de Biochimie Biologie Moléculaire, 13288, Marseille, France

    N. Beaufils & J. Gabert

  7. Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Service d’Hématologie, 13005, Marseille, France

    P. Suchon

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  1. R. Ragheb
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Contributions

BKP and RTC initiated the Sézary project and RTC supervised hospital collaborations. PP supplied characterized PBMC samples from SS patients. BKP conceived the experiments; BKP, BL, JG, and NB (Beaufils) designed the experiments; and BKP, BL, NB (Beaufils), NB (Bonnet), RC, and TLT carried out the experiments. PR designed the statistical analyses of microarray data and RR carried out the bioinformatic analyses. BKP carried out the interpretation of the analyses and drafted the article. PR, RR, VG, and RTC corrected the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Régis T. Costello.

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Conflict of interest

All the authors have no conflicts of interest to declare.

Consent

Patients have signed written informed consent before Sézary cell collection.

Ethical approval

The study was approved by the “Comité de Protection des Personnes” (CPP) Sud-Méditerranée II (ethics committee).

Funding

All the authors have no funding to declare.

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Ragheb, R., Venton, G., Chelbi, R. et al. Vorinostat and Mithramycin A in combination therapy as an interesting strategy for the treatment of Sézary T lymphoma: a transcriptomic approach. Arch Dermatol Res 309, 611–623 (2017). https://doi.org/10.1007/s00403-017-1761-0

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