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

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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Article dans une revue
Archives of Dermatological Research, 2017, 〈10.1007/s00403-017-1761-0〉
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https://hal-amu.archives-ouvertes.fr/hal-01595894
Contributeur : Lionel Spinelli <>
Soumis le : mercredi 27 septembre 2017 - 10:07:37
Dernière modification le : jeudi 29 mars 2018 - 17:28:01

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R. Ragheb, G. Venton, R. Chelbi, N. Bonnet, T. Le Treut, et al.. Vorinostat and Mithramycin A in combination therapy as an interesting strategy for the treatment of Sézary T lymphoma: a transcriptomic approach. Archives of Dermatological Research, 2017, 〈10.1007/s00403-017-1761-0〉. 〈hal-01595894〉

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