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Jatrophane diterpenes from Euphorbia spp. as modulators of multidrug resistance in cancer therapy

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Abstract

A phytochemical investigation of the aerial parts of Euphorbia spp., considered one of the most common elements of Mediterranean landascape, led to the isolation of a large number of bioactive plant metabolites, belonging to the diterpenes family. Above all, over seventy jatrophane, modified jatrophane, segetane, pepluane, and paraliane diterpenoids, fifty of them reported for the first time, were extracted, purified and characterized from Euphorbia dendroides, Euphorbia characias, Euphorbia peplus, Euphorbia paralias and Euphorbia helioscopia. These compounds showed interesting pharmacological activities. In particular, jatrophanes, modified jatrophanes and lathyranes exhibited a potent inhibitory activity against P-glycoprotein (Pgp), a membrane protein that confers cellular ability to resist lethal doses of certain cytotoxic drugs by pumping them to the outside, thus resulting in a reduced cytotoxicity. Among the others, our chemical survey led to isolation of the most powerful inhibitors of daunomycin-efflux activity isolated to date for this class of inhibitors, named euphodendroidin D and pepluanin A. Their efficiency was found to be at least two-fold higher than the conventional modulator cyclosporin A, taken as a reference. In addition, the isolation of a high number of natural structurally-related analogues allowed us to perform Structure Activity Relationship (SAR) studies, without any chemical modification, which gave information on the key pharmacophoric elements of these new class of promising drugs. A further set of diterpene analogues, very recently isolated from sun spurge, E. helioscopia, individually investigated for their Pgp- and BCRP-inhibiting properties, appeared to be specific inhibitors of Pgp since they showed no significant activity against BCRP, thus resembling to the third-generation class of specific MDR inhibitors.

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Acknowledgments

This work was supported by FIRB2003-RBNE03B8 K (Progetto Riconoscimento Molecolare nelle Interazioni Proteina-Ligando) and by CNRS and Université Lyon 1 (UMR 5086) and grants from the Agence Nationale de la Recherche (ANR-06-BLAN-0420), the Association pour la Recherche sur le Cancer (ARC 3942), and the Ligue Nationale contre le Cancer (Equipe labelisée Ligue 2009).

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Authors and Affiliations

  1. DISTAAM, Università degli Studi del Molise, Via F. De Sanctis, 86100, Campobasso, Italy

    G. Corea & V. Lanzotti

  2. Equipe labelisée Ligue 2009, Institut de Biologie et Chimie des Protéines, UMR5086 CNRS-Université Lyon 1, 7 Passage du Vercors, 69367, Lyon Cedex 07, France

    A. Di Pietro

  3. Inserm U590, Lyon, F-69008, France

    C. Dumontet

  4. Université Lyon 1, ISPB, Lyon, F-69003, France

    C. Dumontet

  5. Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli “Federico II”, Via D. Montesano 49, 80131, Naples, Italy

    E. Fattorusso

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  1. G. Corea
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Correspondence to E. Fattorusso.

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Corea, G., Di Pietro, A., Dumontet, C. et al. Jatrophane diterpenes from Euphorbia spp. as modulators of multidrug resistance in cancer therapy. Phytochem Rev 8, 431–447 (2009). https://doi.org/10.1007/s11101-009-9126-8

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