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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

Caspase activity of HL-60 cells after VAE treatment.A. HL-60 cells were incubated for 18 h with VAE. Caspase-8 and-9 activity was measured by FITC-LEHD and FITC-IETD and flow cytometry, ±SD, n = 3. VAEs show a dose-dependent activation of caspase-8 and -9, viscumTT activates the caspases in a synergistic manner. * Fp>1, displays the synergistic effect. B. The cells were treated with TT, viscum or viscumTT for 18 h in the presence or absence of 100 μM z-VAD-fmk, z-IETD-fmk or z-LEHD-fmk. Effects of caspase inhibitors were analyzed by Annexin V/ propidium iodide staining and flow cytometry, ±SD, n = 3. Inhibition of caspase-8 reduces VAE-induced apoptosis by up to 55%, treatment with pan-caspase inhibitor shows an inhibition of apoptosis by up to 75%.
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pone.0133892.g003: Caspase activity of HL-60 cells after VAE treatment.A. HL-60 cells were incubated for 18 h with VAE. Caspase-8 and-9 activity was measured by FITC-LEHD and FITC-IETD and flow cytometry, ±SD, n = 3. VAEs show a dose-dependent activation of caspase-8 and -9, viscumTT activates the caspases in a synergistic manner. * Fp>1, displays the synergistic effect. B. The cells were treated with TT, viscum or viscumTT for 18 h in the presence or absence of 100 μM z-VAD-fmk, z-IETD-fmk or z-LEHD-fmk. Effects of caspase inhibitors were analyzed by Annexin V/ propidium iodide staining and flow cytometry, ±SD, n = 3. Inhibition of caspase-8 reduces VAE-induced apoptosis by up to 55%, treatment with pan-caspase inhibitor shows an inhibition of apoptosis by up to 75%.

Mentions: For more detailed experiments, the activation of caspase-8 and -9 was assessed in VAE-treated HL-60 cells. Both caspases are upstream initiator protease caspases, which play key roles in the extrinsic (caspase-8) or the intrinsic (caspase-9) apoptotic pathway. The data in Fig 3A revealed a similar activation of both caspases by TT and viscum in a concentration-dependent manner. In addition, viscumTT-treated cells activated caspase-8 and -9 in a synergistic way as shown before (*Fp>1).


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)

Caspase activity of HL-60 cells after VAE treatment.A. HL-60 cells were incubated for 18 h with VAE. Caspase-8 and-9 activity was measured by FITC-LEHD and FITC-IETD and flow cytometry, ±SD, n = 3. VAEs show a dose-dependent activation of caspase-8 and -9, viscumTT activates the caspases in a synergistic manner. * Fp>1, displays the synergistic effect. B. The cells were treated with TT, viscum or viscumTT for 18 h in the presence or absence of 100 μM z-VAD-fmk, z-IETD-fmk or z-LEHD-fmk. Effects of caspase inhibitors were analyzed by Annexin V/ propidium iodide staining and flow cytometry, ±SD, n = 3. Inhibition of caspase-8 reduces VAE-induced apoptosis by up to 55%, treatment with pan-caspase inhibitor shows an inhibition of apoptosis by up to 75%.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133892.g003: Caspase activity of HL-60 cells after VAE treatment.A. HL-60 cells were incubated for 18 h with VAE. Caspase-8 and-9 activity was measured by FITC-LEHD and FITC-IETD and flow cytometry, ±SD, n = 3. VAEs show a dose-dependent activation of caspase-8 and -9, viscumTT activates the caspases in a synergistic manner. * Fp>1, displays the synergistic effect. B. The cells were treated with TT, viscum or viscumTT for 18 h in the presence or absence of 100 μM z-VAD-fmk, z-IETD-fmk or z-LEHD-fmk. Effects of caspase inhibitors were analyzed by Annexin V/ propidium iodide staining and flow cytometry, ±SD, n = 3. Inhibition of caspase-8 reduces VAE-induced apoptosis by up to 55%, treatment with pan-caspase inhibitor shows an inhibition of apoptosis by up to 75%.
Mentions: For more detailed experiments, the activation of caspase-8 and -9 was assessed in VAE-treated HL-60 cells. Both caspases are upstream initiator protease caspases, which play key roles in the extrinsic (caspase-8) or the intrinsic (caspase-9) apoptotic pathway. The data in Fig 3A revealed a similar activation of both caspases by TT and viscum in a concentration-dependent manner. In addition, viscumTT-treated cells activated caspase-8 and -9 in a synergistic way as shown before (*Fp>1).

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