Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.

Cytotoxic saponins and other natural products from flowering tops of Narthecium ossifragum L.

For more than four centuries, the intake of Narthecium ossifragum has been associated with poisoning in domesticated animals. Saponins occurring in flowering tops of the plant are considered to cause kidney damage in calves. At present, there are more than 30 papers on the saponins of N. ossifragum in the literature, although the structures of these compounds have hitherto not been determined. Here, we identify the saponins of N. ossifragum as sarsasapogenin, sarsasapogenin-3-O-ß-galactopyranoside, sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-ß-galactopyranoside) and sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-3'-O-α-arabinopyranosyl-ß-galactopyranoside). Moreover, six aromatic natural products were isolated and characterized from the methanolic extract from flowers of N. ossifragum. Five of these aromatic compounds, chrysoeriol 6-C-ß-arabinofuranoside-8-C-ß-glucopyranoside, chrysoeriol 6-C-ß-arabinopyranosyl-8-C-ß-glucopyranoside, chrysoeriol 6-C-ß-xylopyranosyl-8-C-ß-galactopyranoside, chrysoeriol 6-C-ß-galactopyranosyl-8-C-ß-glucopyranoside and chrysoeriol 6-C-ß-glucopyranosyl-8-C-ß-galactopyranoside are undescribed. All compounds were tested for cytotoxicity in mammalian cell lines derived from the heart, kidney, and haematological tissues. The saponins exhibited cytotoxicity in the micromolar range, with proportionally increasing cytotoxicity with increasing number of glycosyl substituents. The most potent compound was the main saponin sarsasapogenin-3-O-(2'-O-ß-glucopyranosyl-3'-O-α-arabinopyranosyl-ß-galactopyranoside), which produced cell death at concentrations below 3-4 µM in all three cell lines tested. This indicates that the saponins are the toxicants mainly responsible for kidney damage observed in cattle after ingestion of N. ossifragum. Our findings also pave the way for analysis of individual compounds isolated during the biopsies of intoxicated animals.