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A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo.

Delebinski CI, Twardziok M, Kleinsimon S, Hoff F, Mulsow K, Rolff J, Jäger S, Eggert A, Seifert G - PLoS ONE (2015)

Bottom Line: Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts.Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice.These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité -Universitaetsmedizin, Berlin, Germany.

ABSTRACT
Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.

No MeSH data available.


Related in: MedlinePlus

Expression of apoptosis associated proteins in HL-60 cells after VAE treatment.A. HL-60 cells were treated with depicted VAE concentrations (~IC50) for 18 h. Cell lysates were incubated with a human apoptosis array detecting the relative expression of apoptosis-related proteins per sample. Each experiment was carried out in duplicate (n = 2). VAE treatment changes the expression of apoptosis associated proteins resulting in an increase of TRAIL-R1 and a decrease in several proteins including XIAP, survivin, claspin and p53. B. The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot. C. Activity of TRAIL-receptor-1 and -2 was measured by FITC-labelled monoclonal antibody and flow cytometry after treatment of HL-60 cells with distinct VAE concentrations for 18 h.
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pone.0133892.g004: Expression of apoptosis associated proteins in HL-60 cells after VAE treatment.A. HL-60 cells were treated with depicted VAE concentrations (~IC50) for 18 h. Cell lysates were incubated with a human apoptosis array detecting the relative expression of apoptosis-related proteins per sample. Each experiment was carried out in duplicate (n = 2). VAE treatment changes the expression of apoptosis associated proteins resulting in an increase of TRAIL-R1 and a decrease in several proteins including XIAP, survivin, claspin and p53. B. The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot. C. Activity of TRAIL-receptor-1 and -2 was measured by FITC-labelled monoclonal antibody and flow cytometry after treatment of HL-60 cells with distinct VAE concentrations for 18 h.

Mentions: To further elucidate the effect of VAE-induced apoptosis on apoptosis relevant proteins, a human apoptosis array was performed with HL-60 cells (VAE concentration ~IC50). We observed a decrease in inhibitor of apoptosis proteins (IAPs) cIAP-1, -2, livin, XIAP and survivin in TT, viscum and viscumTT—treated cells. Here, the most marked reduction of these proteins was observed after viscumTT-treatment (Fig 4A). Claspin, a protein which is required for efficient DNA replication during the S phase, also showed reduced expression in all VAE-treated cells. Furthermore, an increase in TRAIL-R1 (DR4) and -R2 (DR5) was detected, especially after viscumTT-treatment. Besides, a decrease in the mitochondrial pro-apoptotic proteins Bax, Bad, Omi/HtrA2 and Smac/Diablo and the apoptosis adaptor protein FADD was observed. Moreover, expression of the cell cycle inhibitors p21, p27 and p53 was reduced (Fig 4A). The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot for all three extracts (Fig 4B).


A Natural Combination Extract of Viscum album L. Containing Both Triterpene Acids and Lectins Is Highly Effective against AML In Vivo.

Delebinski CI, Twardziok M, Kleinsimon S, Hoff F, Mulsow K, Rolff J, Jäger S, Eggert A, Seifert G - PLoS ONE (2015)

Expression of apoptosis associated proteins in HL-60 cells after VAE treatment.A. HL-60 cells were treated with depicted VAE concentrations (~IC50) for 18 h. Cell lysates were incubated with a human apoptosis array detecting the relative expression of apoptosis-related proteins per sample. Each experiment was carried out in duplicate (n = 2). VAE treatment changes the expression of apoptosis associated proteins resulting in an increase of TRAIL-R1 and a decrease in several proteins including XIAP, survivin, claspin and p53. B. The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot. C. Activity of TRAIL-receptor-1 and -2 was measured by FITC-labelled monoclonal antibody and flow cytometry after treatment of HL-60 cells with distinct VAE concentrations for 18 h.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526680&req=5

pone.0133892.g004: Expression of apoptosis associated proteins in HL-60 cells after VAE treatment.A. HL-60 cells were treated with depicted VAE concentrations (~IC50) for 18 h. Cell lysates were incubated with a human apoptosis array detecting the relative expression of apoptosis-related proteins per sample. Each experiment was carried out in duplicate (n = 2). VAE treatment changes the expression of apoptosis associated proteins resulting in an increase of TRAIL-R1 and a decrease in several proteins including XIAP, survivin, claspin and p53. B. The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot. C. Activity of TRAIL-receptor-1 and -2 was measured by FITC-labelled monoclonal antibody and flow cytometry after treatment of HL-60 cells with distinct VAE concentrations for 18 h.
Mentions: To further elucidate the effect of VAE-induced apoptosis on apoptosis relevant proteins, a human apoptosis array was performed with HL-60 cells (VAE concentration ~IC50). We observed a decrease in inhibitor of apoptosis proteins (IAPs) cIAP-1, -2, livin, XIAP and survivin in TT, viscum and viscumTT—treated cells. Here, the most marked reduction of these proteins was observed after viscumTT-treatment (Fig 4A). Claspin, a protein which is required for efficient DNA replication during the S phase, also showed reduced expression in all VAE-treated cells. Furthermore, an increase in TRAIL-R1 (DR4) and -R2 (DR5) was detected, especially after viscumTT-treatment. Besides, a decrease in the mitochondrial pro-apoptotic proteins Bax, Bad, Omi/HtrA2 and Smac/Diablo and the apoptosis adaptor protein FADD was observed. Moreover, expression of the cell cycle inhibitors p21, p27 and p53 was reduced (Fig 4A). The down-regulation of survivin, XIAP, p53 and claspin was confirmed by Western blot for all three extracts (Fig 4B).

Bottom Line: Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts.Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice.These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatric Oncology/Haematology, Otto Heubner Centre for Paediatric and Adolescent Medicine (OHC), Charité -Universitaetsmedizin, Berlin, Germany.

ABSTRACT
Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.

No MeSH data available.


Related in: MedlinePlus