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Marine compounds inhibit growth of multiple myeloma in vitro and in vivo.

Steiner N, Ribatti D, Willenbacher W, Jöhrer K, Kern J, Marinaccio C, Aracil M, García-Fernández LF, Gastl G, Untergasser G, Gunsilius E - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Tumor Biology & Angiogenesis, Innsbruck Medical University, Innsbruck, Austria.

ABSTRACT

Purpose: 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.

Experimental design: 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.

Results: 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.

No MeSH data available.


Related in: MedlinePlus

Anti-angiogenic activities of marine-derived compounds in the gelatin sponge assay(A) CAMs were incubated with gelatin sponges loaded with SFM (left) and with conditioned medium of multiple myeloma-derived endothelial cells either alone (co.) or supplemented with 0.1 nM of marine-derived compounds (drug). Note the decreased number of blood vessels. Images were acquired with a stereomicroscope (magnification, x 50). (B) A set of marine-derived compounds tested at 0.1 nM demonstrated anti-angiogenic activity in response to conditioned media of endothelial cells deriving from patients suffering from multiple myeloma (p <0.05). The mean number of vessels in the control was 24±6. Stars indicate p values <0.05.
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Figure 3: Anti-angiogenic activities of marine-derived compounds in the gelatin sponge assay(A) CAMs were incubated with gelatin sponges loaded with SFM (left) and with conditioned medium of multiple myeloma-derived endothelial cells either alone (co.) or supplemented with 0.1 nM of marine-derived compounds (drug). Note the decreased number of blood vessels. Images were acquired with a stereomicroscope (magnification, x 50). (B) A set of marine-derived compounds tested at 0.1 nM demonstrated anti-angiogenic activity in response to conditioned media of endothelial cells deriving from patients suffering from multiple myeloma (p <0.05). The mean number of vessels in the control was 24±6. Stars indicate p values <0.05.

Mentions: To investigate whether marine-derived compounds could also inhibit myeloma-related angiogenesis, we tested all compounds in the in vivo CAM assay. Sponges soaked with conditioned medium of bone marrow-derived endothelial cells from patients with MM were grafted with compounds S1-S9 on chicken chorioallantoic membranes (CAMs). CAMs implanted with a gelatin sponge together with conditioned medium were surrounded by a rim of newly formed capillaries converging radially toward the sponge in a “spoked-wheel” pattern (mean number of vessels: 24±6; Figure 3A; with serum-free medium: mean number of vessels: 9±2). Marine-derived compounds applied at low nM concentrations markedly inhibited the formation of capillaries (Figure 3A). Addition of compounds at even a concentration of 0.1 nM resulted in a significant inhibition of MM endothelial cell-induced angiogenesis for Plitidepsin, Zalypsis, PM00113, PM01215 and PM02781 (Figure 3B).


Marine compounds inhibit growth of multiple myeloma in vitro and in vivo.

Steiner N, Ribatti D, Willenbacher W, Jöhrer K, Kern J, Marinaccio C, Aracil M, García-Fernández LF, Gastl G, Untergasser G, Gunsilius E - Oncotarget (2015)

Anti-angiogenic activities of marine-derived compounds in the gelatin sponge assay(A) CAMs were incubated with gelatin sponges loaded with SFM (left) and with conditioned medium of multiple myeloma-derived endothelial cells either alone (co.) or supplemented with 0.1 nM of marine-derived compounds (drug). Note the decreased number of blood vessels. Images were acquired with a stereomicroscope (magnification, x 50). (B) A set of marine-derived compounds tested at 0.1 nM demonstrated anti-angiogenic activity in response to conditioned media of endothelial cells deriving from patients suffering from multiple myeloma (p <0.05). The mean number of vessels in the control was 24±6. Stars indicate p values <0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480745&req=5

Figure 3: Anti-angiogenic activities of marine-derived compounds in the gelatin sponge assay(A) CAMs were incubated with gelatin sponges loaded with SFM (left) and with conditioned medium of multiple myeloma-derived endothelial cells either alone (co.) or supplemented with 0.1 nM of marine-derived compounds (drug). Note the decreased number of blood vessels. Images were acquired with a stereomicroscope (magnification, x 50). (B) A set of marine-derived compounds tested at 0.1 nM demonstrated anti-angiogenic activity in response to conditioned media of endothelial cells deriving from patients suffering from multiple myeloma (p <0.05). The mean number of vessels in the control was 24±6. Stars indicate p values <0.05.
Mentions: To investigate whether marine-derived compounds could also inhibit myeloma-related angiogenesis, we tested all compounds in the in vivo CAM assay. Sponges soaked with conditioned medium of bone marrow-derived endothelial cells from patients with MM were grafted with compounds S1-S9 on chicken chorioallantoic membranes (CAMs). CAMs implanted with a gelatin sponge together with conditioned medium were surrounded by a rim of newly formed capillaries converging radially toward the sponge in a “spoked-wheel” pattern (mean number of vessels: 24±6; Figure 3A; with serum-free medium: mean number of vessels: 9±2). Marine-derived compounds applied at low nM concentrations markedly inhibited the formation of capillaries (Figure 3A). Addition of compounds at even a concentration of 0.1 nM resulted in a significant inhibition of MM endothelial cell-induced angiogenesis for Plitidepsin, Zalypsis, PM00113, PM01215 and PM02781 (Figure 3B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Tumor Biology & Angiogenesis, Innsbruck Medical University, Innsbruck, Austria.

ABSTRACT

Purpose: 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.

Experimental design: 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.

Results: 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.

No MeSH data available.


Related in: MedlinePlus