Antimyeloma activity of the sesquiterpene lactone cnicin: impact on Pim-2 kinase as a novel therapeutic target

Abstract

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.

Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation

“…[43][44][45] Some of the compounds have demonstrated activities in both cell lines and xenograft models, including both hematologic and solid tumor models. [46][47][48] Here, our findings strongly support the potential of targeting Pim2 in MM patients and suggest that a potent small-molecule Pim2 (or pan-Pim) inhibitor holds promise as an effective targeted therapy in MM. Indeed, our potent and selective Pim kinase inhibitor LGB321 showed significant suppression of MM cell growth both in vitro and in vivo.…”

Secondary metabolites of three endemic Centaurea L. species

“…Known to be cytotoxic as some other sesquiterpene lactones, 30 cnicin exhibited cytotoxic activity against some tumor cell lines including leukemia (HL-60), hepatomas, sarcomas, lymphoid leukemia and multiple myeloma. [31][32][33][34] Available on line at www.shd.org.rs/JSCS/ In previous phytochemical studies, the content of cnicin in six Centaurea species was analyzed by 1 H-NMR spectroscopy. The examined extracts were made from freshly collected plants.…”

CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

“…Instead of a mouse model, we here chose a chick chorioallantoic membrane (CAM) assay modified for the use with human myeloma cells as previously reported [26, 27]. This model has also been successfully utilized to investigate tumor-stroma interactions in other human B-cell malignancies [28, 29].…”