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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

Multiple Myeloma Xenograft Model(A) OPM-2eGFP and RPMI-8226eGFP cells were mixed with primary human bone-marrow mesenchymal cells, collagen type I as extracellular matrix component and with 1 nM of the respective target compound and grafted on the chorioallantoic membrane of chicken embryos (n=3). After five days tumors can be visualized by eGFP expression. In grafts, all drugs showed significant lower fluorescence than the control. Bars indicate 500 μm. (B) Single MM xenografts were excised and homogenized in lysis buffer and subsequently measured using a GFP ELISA. GFP concentrations of single tumors were calculated (n=6, Mean ± SEM). Stars indicate p values <0.05. con.: control.
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Figure 2: Multiple Myeloma Xenograft Model(A) OPM-2eGFP and RPMI-8226eGFP cells were mixed with primary human bone-marrow mesenchymal cells, collagen type I as extracellular matrix component and with 1 nM of the respective target compound and grafted on the chorioallantoic membrane of chicken embryos (n=3). After five days tumors can be visualized by eGFP expression. In grafts, all drugs showed significant lower fluorescence than the control. Bars indicate 500 μm. (B) Single MM xenografts were excised and homogenized in lysis buffer and subsequently measured using a GFP ELISA. GFP concentrations of single tumors were calculated (n=6, Mean ± SEM). Stars indicate p values <0.05. con.: control.

Mentions: EGFP-transgenic myeloma cells (OPM-2eGFP and RPMI-8226eGFP) together with ex vivo-derived human bone-marrow mesenchymal cells were embedded in collagen type I as extracellular matrix component. Test substances were applied topically at 1 nM concentration. These “onplants” were grafted on the chorioallantoic membrane of chicken embryos (using six replicates). After five days, MM xenografts formed tumors that could be visualized by eGFP expression (Figure 2A). Compared to controls (0.1% DMSO), all analyzed target compounds inhibited growth of MM cells in xenografts resulting in less green-fluorescent MM tumor cell mass (Figure 2A). Single MM xenografts (n=6/group) were excised, homogenized and thereafter measured by GFP ELISA. All tested compounds significantly reduced myeloma cell mass in a manner similar to that observed for bortezomib (Figure 2B). Again Zalypsis and PM00113 were the most potent inhibitors of myeloma growth in vivo, exceeding even the anti-myeloma activity of bortezomib.


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)

Multiple Myeloma Xenograft Model(A) OPM-2eGFP and RPMI-8226eGFP cells were mixed with primary human bone-marrow mesenchymal cells, collagen type I as extracellular matrix component and with 1 nM of the respective target compound and grafted on the chorioallantoic membrane of chicken embryos (n=3). After five days tumors can be visualized by eGFP expression. In grafts, all drugs showed significant lower fluorescence than the control. Bars indicate 500 μm. (B) Single MM xenografts were excised and homogenized in lysis buffer and subsequently measured using a GFP ELISA. GFP concentrations of single tumors were calculated (n=6, Mean ± SEM). Stars indicate p values <0.05. con.: control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Multiple Myeloma Xenograft Model(A) OPM-2eGFP and RPMI-8226eGFP cells were mixed with primary human bone-marrow mesenchymal cells, collagen type I as extracellular matrix component and with 1 nM of the respective target compound and grafted on the chorioallantoic membrane of chicken embryos (n=3). After five days tumors can be visualized by eGFP expression. In grafts, all drugs showed significant lower fluorescence than the control. Bars indicate 500 μm. (B) Single MM xenografts were excised and homogenized in lysis buffer and subsequently measured using a GFP ELISA. GFP concentrations of single tumors were calculated (n=6, Mean ± SEM). Stars indicate p values <0.05. con.: control.
Mentions: EGFP-transgenic myeloma cells (OPM-2eGFP and RPMI-8226eGFP) together with ex vivo-derived human bone-marrow mesenchymal cells were embedded in collagen type I as extracellular matrix component. Test substances were applied topically at 1 nM concentration. These “onplants” were grafted on the chorioallantoic membrane of chicken embryos (using six replicates). After five days, MM xenografts formed tumors that could be visualized by eGFP expression (Figure 2A). Compared to controls (0.1% DMSO), all analyzed target compounds inhibited growth of MM cells in xenografts resulting in less green-fluorescent MM tumor cell mass (Figure 2A). Single MM xenografts (n=6/group) were excised, homogenized and thereafter measured by GFP ELISA. All tested compounds significantly reduced myeloma cell mass in a manner similar to that observed for bortezomib (Figure 2B). Again Zalypsis and PM00113 were the most potent inhibitors of myeloma growth in vivo, exceeding even the anti-myeloma activity of bortezomib.

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