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.