Simalikalactone E (SkE), a new weapon in the armamentarium of drugs targeting cancers that exhibit constitutive activation of the ERK pathway

Abstract

// Guillaume Robert 1,2,3,4 , Valérie Jullian 6,7 , Arnaud Jacquel 1,2,3,4 , Clémence Ginet 1,2,3,4 , Maeva Dufies 1,2,3,4 , Stephanie Torino 1,4,5 , Anaïs Pottier 1,4,8 , Frederic Peyrade 9 , Sophie Tartare-Deckert 1,4,8 , Geneviève Bourdy 6,7 , Eric Deharo 6,7 and Patrick Auberger 1,2,3,4 1- INSERM/U1065, C3M, Nice, France 2- Equipe 2 : Morts Cellulaires, Différenciation, inflammation et Cancer 3- Equipe labellisée par la Ligue Nationale Contre le Cancer 2011-2013 4- Université de Nice, France 5- Equipe 6 : Toxines microbiennes dans la relation hôte-pathogènes 6- Université de Toulouse; Université Paul Sabatier; Pharma-Dev UMR 152; Faculté de Pharmacie; 35 Chemin des maraîchers, F-31062, Toulouse cedex 9, France. 7- Institut de Recherche pour le Développement (IRD); Pharma-Dev UMR 152; Faculté de Pharmacie, 35 Chemin des maraîchers, F-31062, Toulouse cedex 9, France. 8- Equipe 11, Microenvironnement, Signalisation et Cancer 9- Centre Antoine Lacassagne, Nice, France Correspondence: Patrick Auberger, email: // Keywords : Simalikalactone E, B-Raf inhibitor, CML, Melanoma, Hairy Cell Leukemia, ERK pathway Received : December 20, 2012, Accepted : December 28, 2012, Published : December 30, 2012 Abstract Simalikalactone E (SkE) is a quassinoid extracted from a widely used Amazonian antimalarial remedy. Although SkE has previously been shown to have cytostatic and/or cytotoxic activities in some tumor cell lines, its mechanism of action has not yet been characterized. We show here that SkE in the high nanomolar range inhibited the growth of various leukemic and solid tumor cell lines. Importantly, SkE was highly efficient at inhibiting chronic myelogenous leukemia (CML) cells that exhibit constitutive activation of the MAPK pathway and, accordingly, it impaired the phosphorylation of ERK1/2. SkE also abrogated MEK1/2 and B-Raf phosphorylation but had no effect on Ras activity. Moreover, SkE was particularly effective against melanoma cell lines carrying the B-Raf-V600E mutation. Importantly, SkE resensitized the PLX-4032-resistant 451Lu melanoma cell line (451Lu-R) and was more efficient than U0126, a MEK inhibitor, and PLX-4032 (PLX) at inducing the apoptosis of two Hairy Cell Leukemia (HCL) patient samples carrying the B-Raf-V600E mutation. Finally, SkE was as efficient as imatinib at inhibiting tumor formation in a xenograft model of CML cells in athymic mice. In conclusion, we show that SkE, a very potent inhibitor of B-Raf-V600E, is highly effective against cancer cell lines that exhibit constitutive activation of the ERK1/2 pathway.