Abstract
The prognosis of patients with multiple myeloma (MM) is still dismal despite recent improvements achieved by introducing new therapeutic agents. However, there remains an urgent need for progress in myeloma drug development. We here show that novel marine-derived compounds can exert potent anti-myeloma activity. Nine marine-derived compounds were applied at low nM concentrations (0.1-100 nM) to MM cell lines (OPM-2, NCI-H929, U266, RPMI-8226), to primary human myeloma cells and to peripheral blood mononuclear cells. Apoptosis was determined by flow cytometry. In addition, eGFP-transgenic MM cell lines growing with mesenchymal cells from bone marrow were used to visualize tumors by fluorescence stereomicroscopy. Anti-myelomaactivities were studied in vitro in 3D spheroids and in vivo in myeloma xenografts on chicken embryos. Tumor size was analyzed by measuring GFP content with a GFP ELISA. Anti-angiogenic activities of compounds were tested in an in vivo gelatin sponge assay with conditioned media from primary bone marrow-derived endothelial cells. We identified a subset of marine compounds with strong anti-myeloma activity in vitro and in vivo. Moreover, some of the compounds inhibited myeloma-related angiogenesis in the in vivo gelatin sponge assay. They merit further drug development to improve treatment options for MM.
Highlights
Multiple myeloma (MM) is the second most frequent hematological malignancy [1], a malignant B-cell neoplasm with rising prevalence that causes considerable morbidity, mortality and health care expenditures [2, 3]
Marine compounds were tested for their ability to induce apoptosis in human MM cell lines
Most compounds showed anti-myeloma activity in vitro when tested at concentrations of 100 nM in commercially available human MM cell lines growing under standard culture conditions (Table 1, Supplementary Figure 1)
Summary
Multiple myeloma (MM) is the second most frequent hematological malignancy [1], a malignant B-cell neoplasm with rising prevalence that causes considerable morbidity, mortality and health care expenditures [2, 3]. The last decade has seen considerable improvement in overall and progression-free survival due to the introduction of new drugs as proteasome inhibitors like bortezomib and carfilzomib and immunomodulatory agents including thalidomide, lenalidomide and pomalidomide [4, 5], in most cases MM remains an incurable disease with inevitable disease progression due to clonal evolution, development of drug resistance and fatal outcome [4]. MM cell lines (OPM-2, U266, NCI-H929) were incubated with increasing concentrations of drugs for 24h and analyzed by flow cytometry. Data were calculated from triplicate results for each drug; 10 nM or 100 nM. Highlighted numbers indicate significant killing of myeloma cell lines.
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