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

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 hig...

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Veröffentlicht in:Oncotarget 2012-12, Vol.3 (12), p.1688-1699
Hauptverfasser: Robert, Guillaume, Jullian, Valérie, Jacquel, Arnaud, Ginet, Clémence, Dufies, Maeva, Torino, Stephanie, Pottier, Anaïs, Peyrade, Frederic, Tartare-Deckert, Sophie, Bourdy, Geneviève, Deharo, Eric, Auberger, Patrick
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container_end_page 1699
container_issue 12
container_start_page 1688
container_title Oncotarget
container_volume 3
creator Robert, Guillaume
Jullian, Valérie
Jacquel, Arnaud
Ginet, Clémence
Dufies, Maeva
Torino, Stephanie
Pottier, Anaïs
Peyrade, Frederic
Tartare-Deckert, Sophie
Bourdy, Geneviève
Deharo, Eric
Auberger, Patrick
description 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.
doi_str_mv 10.18632/oncotarget.791
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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. 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Finally, SkE was as efficient as imatinib at inhibiting tumor formation in a xenograft model of CML cells in athymic mice. 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subjects Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases - metabolism
Female
HEK293 Cells
Humans
K562 Cells
Leukemia, Hairy Cell - enzymology
Leukemia, Hairy Cell - genetics
Leukemia, Hairy Cell - pathology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Life Sciences
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - metabolism
Melanoma - enzymology
Melanoma - genetics
Melanoma - pathology
Mice
Mice, Nude
Molecular Targeted Therapy
Mutation
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - metabolism
Quassins - pharmacology
Research Papers
Signal Transduction - drug effects
Skin Neoplasms - enzymology
Skin Neoplasms - genetics
Skin Neoplasms - pathology
Time Factors
Transfection
Tumor Burden - drug effects
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
title Simalikalactone E (SkE), a new weapon in the armamentarium of drugs targeting cancers that exhibit constitutive activation of the ERK pathway
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