Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target.
Despite recent advances in therapy, multiple myeloma, the second most common hematologic tumor in the Western world, is still incurable. Identification of substances that display a wide range of tumor-killing activities and target cancer-specific pathways constitute a basis for the development of novel therapies. In this study, we investigate the cytotoxic effect of the natural substance cnicin in multiple myeloma. Cnicin treatment reveals potent antiproliferative effects and induces cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells are unaffected. We show that activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. We provide evidence that Pim-2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. Thus, our data indicate that cnicin induces myeloma cell death via several pathways and reveals Pim-2 as a novel target. These findings provide a rational for further evaluation of cnicin as a new anti-tumor drug and underline the potential of sesquiterpene lactones in tumor therapy.
Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria. karin.joehrer@tkfi.at
Karin
K
Jöhrer
Marlene
M
Obkircher
Daniel
D
Neureiter
Johanna
J
Parteli
Claudia
C
Zelle-Rieser
Eva
E
Maizner
Johann
J
Kern
Martin
M
Hermann
Frank
F
Hamacher
Olaf
O
Merkel
Nathalie
N
Wacht
Christian
C
Zidorn
Marcel
M
Scheideler
Richard
R
Greil
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D046228:Microarray Analysis; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D012717:Sesquiterpenes; C012849:cnicin; D017346:Protein Serine-Threonine Kinases