Synergistic Antitumour Properties of viscumTT in Alveolar Rhabdomyosarcoma

Rahel Mascha Stammer, Susann Kleinsimon, Jana Rolff, Sebastian Jäger, Angelika Eggert, Georg Seifert, Catharina I Delebinski, Rahel Mascha Stammer, Susann Kleinsimon, Jana Rolff, Sebastian Jäger, Angelika Eggert, Georg Seifert, Catharina I Delebinski

Abstract

Aqueous mistletoe extracts from the European mistletoe (Viscum album) contain mainly mistletoe lectins and viscotoxins as cytotoxic compounds. Lipophilic triterpene acids, which do not occur in conventional mistletoe preparations, were solubilised with β-cyclodextrins. The combination of an aqueous extract (viscum) and a triterpene-containing extract (TT) recreated a whole mistletoe extract (viscumTT). These extracts were tested on rhabdomyosarcoma in vitro, ex vivo, and in vivo with regard to anticancer effects. Viscum and viscumTT inhibited cell proliferation and induced apoptosis effectively in a dose-dependent manner in vitro and ex vivo, whereas TT showed only moderate inhibitory effects. viscumTT proved to be more effective than the single extracts and displayed a synergistic effect in vitro and a stronger effect in vivo. viscumTT induced apoptosis via the extrinsic and intrinsic pathways, evidenced by the loss of mitochondrial membrane potential and activation of CASP8 and CASP9. CASP10 inhibitor inhibited apoptosis effectively, emphasising the importance of CASP10 in viscumTT-induced apoptosis. Additionally, viscumTT changed the ratio of apoptosis-associated proteins by downregulation of antiapoptotic proteins such as XIAP and BIRC5, thus shifting the balance towards apoptosis. viscumTT effectively reduced tumour volume in patient-derived xenografts in vivo and may be considered a promising substance for rhabdomyosarcoma therapy.

Figures

Figure 1
Figure 1
viscumTT inhibits cell proliferation and induces apoptosis synergistically in ARMS. (a) RMS-13 and RH-30 cells were incubated with viscum, TT, and viscumTT in increasing concentrations for 24 h. Cell proliferation was measured by CASY cell counter analysis, and the proliferation rate was calculated from the total cell numbers compared to untreated control cells. Apoptosis was assessed by annexin V/PI assay, and results were analysed by FlowJo Software. (b) RMS-13 cells were treated with viscum, TT, and viscumTT in increasing concentrations, and early cytotoxicity was measured by LDH assay. Results are presented as percentage of untreated control cells. (c) Apoptosis was confirmed by PARP cleavage. For this purpose, Western blot analyses were performed after treatment of RMS-13 cells with viscum, TT, and viscumTT. β-actin served as a loading control. Results are presented as means ± SD of three independent experiments. Webb's fractional product (Fp) was calculated to assess synergism, values ∗Fp > 1 display synergism. Mistletoe lectin (ML) and oleanolic acid (OA) concentrations were used as marker substances for viscum and TT, respectively.
Figure 2
Figure 2
viscumTT displays synergistic effects on mitochondrial membrane (∆Ψm) depolarisation and activation of CASP3, CASP8, and CASP9. RMS-13 cells were incubated with viscum, TT, and viscumTT in increasing concentrations for 24 h. (a) ∆Ψm depolarisation was analysed by JC-1 staining and flow cytometry. The protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial membrane disruptor, was used as a positive control. (b) Active caspase assays were performed according to the manufacturer's instructions to monitor activation of caspase-3 (CASP3), caspase-8 (CASP8), and caspase-9 (CASP9). All results are presented as means ± SD of three independent experiments. Webb's fractional product (Fp) was calculated to assess synergism, values ∗Fp > 1 display synergism. Mistletoe lectin (ML) and oleanolic acid (OA) concentrations were used as marker substances for viscum and TT, respectively.
Figure 3
Figure 3
Caspase inhibitors effectively reduce viscum- and viscumTT-mediated apoptosis. RMS-13 cells were pretreated with 50–100 μmol of caspase inhibitors Z-VAD-FMK (pan inhibitor), Z-IETD-FMK (caspase-8), Z-LEHD-FMK (caspase-9), or Z-AEVD-FMK (caspase-10) for one hour. Subsequently, cells were treated with viscum, TT, and viscumTT for 24 h and analysed by annexin/PI assay and flow cytometry. Results are presented as percentage of untreated control cells and means ± SD of three independent experiments. Mistletoe lectin (ML) and oleanolic acid (OA) concentrations were used as marker substances for viscum and TT, respectively.
Figure 4
Figure 4
viscumTT alters the expression of antiapoptotic proteins. RMS-13 cells were treated with viscum, TT, and viscumTT in increasing concentrations for 24 h. Afterwards, cells were lysed and whole proteins lysates were analysed by Western blot for altered expression of X-linked inhibitor of apoptosis protein (XIAP), baculoviral IAP repeat containing 5 (BIRC5), myeloid cell leukemia 1 (MCL1), B-cell lymphoma 2 (BCL2), and BCL2 like 1 (BCL2L1). β-actin served as a loading control. Mistletoe lectin (ML) and oleanolic acid (OA) concentrations were used as marker substances for viscum and TT, respectively.
Figure 5
Figure 5
viscumTT induces apoptosis synergistically ex vivo. Ex vivo cultures from three different patients were incubated with viscum, TT, and viscumTT in increasing concentrations for 48 h (a) patient no. 1 or for 24 h, (b) patient no. 2, and (c) patient no. 3. Cell proliferation was measured by CASY cell counter analysis, and apoptosis was assessed by annexin V/PI assay and flow cytometry. All results are presented as means ± SD of two independent experiments. Webb's fractional product (∗Fp) was calculated to assess synergism, values ∗Fp > 1 display synergism. Mistletoe lectin (ML) and oleanolic acid (OA) concentrations were used as marker substances for viscum and TT, respectively.
Figure 6
Figure 6
viscumTT effectively reduces tumour volume in patient-derived RMS xenografts. Patient-derived RMS cells from (a) patient no. 1 and (b) patient no. 2 were used for s.c. implantation in the inguinal region of mice. Treatment started on day 12 when tumours were palpable, with (a) i.t. administration of viscum, TT, viscumTT, cyclodextrins (CD; control group), and i.v. doxorubicin (Doxo) and (b) i.t. administration of viscumTT and i.v. treatment with viscumTT and cyclodextrins. The mice were treated every two-three days in rising concentrations, and each dose was given twice. The administered concentrations were 40/60/80 mg/kg oleanolic acid (TT), 0.5/1.0/1.5 μg/kg mistletoe lectin (viscum), or a combination thereof (viscumTT). Two-way ANOVA and Bonferroni post hoc tests were applied to determine differences between mouse xenograft treatment groups (∗∗p ≤ 0.01).
Figure 7
Figure 7
Scheme for viscumTT-induced apoptosis via the extrinsic and the intrinsic signalling pathways. Through yet unknown mechanisms, viscumTT activates caspase-8 (CASP8) and caspase-10 (CASP10), resulting in an activation of the caspase cascade. Caspase-9 (CASP9) acts as an effector downstream of CASP8 and CASP10 rather than an initiator of apoptosis. Further, viscumTT downregulates antiapoptotic proteins B-cell lymphoma 2 (BCL2), BCL2 like 1 (BCL2L1), and myeloid cell leukemia 1 (MCL1) as well as inhibitors of apoptosis proteins baculoviral IAP repeat containing 5 (BIRC5) and X-linked inhibitor of apoptosis protein (XIAP), thus shifting the balance towards apoptosis.

References

    1. Kaatsch P., Spix C. German Childhood Cancer Registry - Annual Report 2015 (1980–2014). Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz. Mainz: Deutsches Kinderkrebsregister; 2015.
    1. Hawkins D. S., Gupta A. A., Rudzinski E. What’s new in the Biology and treatment of pediatric rhabdomyosarcoma? Current Opinion in Pediatrics. 2014;26(1):50–56. doi: 10.1097/MOP.0000000000000041.
    1. Dagher R., Helman L. Rhabdomyosarcoma: an overview. The Oncologist. 1999;4(1):34–44.
    1. Monti E., Fanzani A. Uncovering metabolism in rhabdomyosarcoma. Cell Cycle. 2016;15(2):184–195. doi: 10.1080/15384101.2015.1071746.
    1. Mercado G. E., Barr F. G. Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances. Current Molecular Medicine. 2007;7(1):47–61. doi: 10.2174/156652407779940440.
    1. Barr F. G., Galili N., Holick J., Biegel J. A., Rovera G., Emanuel B. S. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nature Genetics. 1993;3(2):113–117. doi: 10.1038/ng0293-113.
    1. Sorensen P. H., Lynch J. C., Qualman S. J., et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. Journal of Clinical Oncology. 2002;20(11):2672–2679. doi: 10.1200/JCO.2002.03.137.
    1. Hawkins D. S., Spunt S. L., Skapek S. X. Children’s oncology group’s 2013 blueprint for research: soft tissue sarcomas. Pediatric Blood & Cancer. 2013;60(6):1001–1008. doi: 10.1002/pbc.24435.
    1. Sokolowski E., Turina C. B., Kikuchi K., Langenau D. M., Keller C. Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. Oncogene. 2014;33(15):1877–1889.
    1. Hettmer S., Li Z., Billin A. N., et al. Rhabdomyosarcoma: current challenges and their implications for developing therapies. Cold Spring Harbor Perspectives in Medicine. 2014;4(11, article a025650)
    1. Franz H., Ziska P., Kindt A. Isolation and properties of three lectins from mistletoe (Viscum album L.) The Biochemical Journal. 1981;195(2):481–484. doi: 10.1042/bj1950481.
    1. Winterfeld K., Bijl L. H. Viscotoxin, ein neuer Inhaltsstoff der Mistel (Viscum album L) European Journal of Organic Chemistry. 1949;561(2):107–115.
    1. Samuelsson G. Mistletoe Toxins. Systematic Biology. 1973;22(4):566–569.
    1. Urech K., Schaller G., Ziska P. Comparative study on the cytotoxic effect of viscotoxin and mistletoe lectin on tumour cells in culture. Phytotherapy Research. 1995;9(1):49–55. doi: 10.1002/ptr.2650090112.
    1. Wagner H., Feil B., Bladt S. Viscum album - die Mistel - Analyse und Standardisierung von Arzneidrogen und Phytopräparaten durch Hochleistungsflüssigchromatographie (HPLC) und andere chromatographische Verfahren (III) Deutsche Apotheker Zeitung; 1984. pp. 1429–1432.
    1. Fukunaga T., Kajikawa I., Nishiya K., Watanabe Y., Takeya K., Itokawa H. Studies on the constituents of the European mistletoe, Viscum album L. Chemical & Pharmaceutical Bulletin. 1987;35(8):3292–3297. doi: 10.1248/cpb.35.3292.
    1. Becker H., Exner J., Schilling G. Notizen: Isolierung und Strukturaufklärung von 2′-Hydroxy-4′, 6′dimethoxychalkon-4-glukosid aus Viscum album L. / isolation and identification of 2′-hydroxy-4′, 6′ -dimethoxy-chalkon-4-glucoside of Viscum album L. Zeitschrift für Naturforschung C. 1978;33(9-10):771–773.
    1. Becker H., Exner J. Vergleichende Untersuchungen von Misteln verschiedener Wirtsbäume an Hand der Flavonoide and Phenolcarbonsäuren. Zeitschrift für Pflanzenphysiologie. 1980;97(5):417–428. doi: 10.1016/S0044-328X(80)80016-X.
    1. Jordan E., Wagner H. Structure and properties of polysaccharides from Viscum album (L.) Oncology. 1986;43(Supplement 1):8–15.
    1. Klett C. Y., Anderer F. A. Activation of natural killer cell cytotoxicity of human blood monocytes by a low molecular weight component from Viscum album extract. Arzneimittel-Forschung. 1989;39(12):1580–1585.
    1. Park Y. K., Do Y. R., Jang B. C. Apoptosis of K562 leukemia cells by Abnobaviscum F(R), a European mistletoe extract. Oncology Reports. 2012;28(6):2227–2232. doi: 10.3892/or.2012.2026.
    1. Kovacs E. Investigation of the proliferation, apoptosis/necrosis, and cell cycle phases in several human multiple myeloma cell lines. Comparison of Viscum album QuFrF extract with vincristine in an in vitro model. ScientificWorldJournal. 2010;10:311–320. doi: 10.1100/tsw.2010.30.
    1. Klingbeil M. F., Xavier F. C., Sardinha L. R., et al. Cytotoxic effects of mistletoe (Viscum album L.) in head and neck squamous cell carcinoma cell lines. Oncology Reports. 2013;30(5):2316–2322. doi: 10.3892/or.2013.2732.
    1. Eggenschwiler J., von Balthazar L., Stritt B., et al. Mistletoe lectin is not the only cytotoxic component in fermented preparations of Viscum album from white fir (Abies Pectinata) BMC Complementary and Alternative Medicine. 2007;7:p. 14.
    1. Seifert G., Jesse P., Laengler A., et al. Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. Cancer Letters. 2008;264(2):218–228. doi: 10.1016/j.canlet.2008.01.036.
    1. Beuth J., Ko H. L., Schneider H., et al. Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model. Anticancer Research. 2006;26(6b):4451–4456.
    1. Duong Van Huyen J. P., Delignat S., Bayry J., et al. Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma. Cancer Letters. 2006;243(1):32–37. doi: 10.1016/j.canlet.2005.11.016.
    1. Rostock M., Huber R., Greiner T., et al. Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Research. 2005;25(3b):1969–1975.
    1. Tröger W., Galun D., Reif M., Schumann A., Stanković N., Milićević M. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. European Journal of Cancer. 2013;49(18):3788–3797. doi: 10.1016/j.ejca.2013.06.043.
    1. Alabran J. L., Cheuk A., Liby K., et al. Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. Cancer Biology & Therapy. 2008;7(5):709–717.
    1. Gao X., Deeb D., Jiang H., Liu Y., Dulchavsky S. A., Gautam S. C. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. Journal of Neuro-Oncology. 2007;84(2):147–157. doi: 10.1007/s11060-007-9364-9.
    1. Zhou R., Zhang Z., Zhao L., et al. Inhibition of mTOR signaling by oleanolic acid contributes to its anti-tumor activity in osteosarcoma cells. Journal of Orthopaedic Research. 2011;29(6):846–852. doi: 10.1002/jor.21311.
    1. Zhang P., Li H., Chen D., Ni J., Kang Y., Wang S. Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly(ADP-ribose) polymerase cleavage. Acta Biochimica et Biophysica Sinica (Shanghai) 2007;39(10):803–809. doi: 10.1111/j.1745-7270.2007.00335.x.
    1. Wu J., Yang C., Guo C., et al. SZC015, a synthetic oleanolic acid derivative, induces both apoptosis and autophagy in MCF-7 breast cancer cells. Chemico-Biological Interactions. 2016;244:94–104. doi: 10.1016/j.cbi.2015.11.013.
    1. Rui L. X., Shu S. Y., Jun W. J., et al. The dual induction of apoptosis and autophagy by SZC014, a synthetic oleanolic acid derivative, in gastric cancer cells via NF-κB pathway. Tumour Biology. 2016;37(4):5133–5144.
    1. Hua Y., Zhang Z., Li J., et al. Oleanolic acid derivative Dex-OA has potent anti-tumor and anti-metastatic activity on osteosarcoma cells in vitro and in vivo. Investigational new Drugs. 2011;29(2):258–265. doi: 10.1007/s10637-009-9354-1.
    1. Li H. F., Wang X. A., Xiang S. S., et al. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Design, Development and Therapy. 2015;9:3017–3030. doi: 10.2147/DDDT.S84448.
    1. Wang X., Bai H., Zhang X., et al. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis. 2013;34(6):1323–1330. doi: 10.1093/carcin/bgt058.
    1. Wei J., Liu M., Liu H., et al. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. Journal of Applied Toxicology. 2013;33(8):756–765. doi: 10.1002/jat.2725.
    1. Jäger S., Winkler K., Pfüller U., Scheffler A. Solubility studies of oleanolic acid and betulinic acid in aqueous solutions and plant extracts of Viscum album L. Planta Medica. 2007;73(2):157–162. doi: 10.1055/s-2007-967106.
    1. Delebinski C. I., Twardziok M., Kleinsimon S., et al. A natural combination extract of Viscum album L. containing both triterpene acids and lectins is highly effective against AML in vivo. PloS One. 2015;10(8, article e0133892)
    1. Delebinski C. I., Jaeger S., Kemnitz-Hassanin K., Henze G., Lode H. N., Seifert G. J. A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. Cell Proliferation. 2012;45(2):176–187. doi: 10.1111/j.1365-2184.2011.00801.x.
    1. Twardziok M., Kleinsimon S., Rolff J., et al. Multiple active compounds from Viscum album L. synergistically converge to promote apoptosis in Ewing sarcoma. PloS One. 2016;11(9, article e0159749)
    1. Kleinsimon S., Kauczor G., Jaeger S., Eggert A., Seifert G., Delebinski C. viscumTT induces apoptosis and alters IAP expression in osteosarcoma in vitro and has synergistic action when combined with different chemotherapeutic drugs. BMC Complementary and Alternative Medicine. 2017;17(1):p. 26.
    1. Strüh C. M., Jäger S., Kersten A., Schempp C. M., Scheffler A., Martin S. F. Triterpenoids amplify anti-tumoral effects of mistletoe extracts on murine B16.f10 melanoma in vivo. PloS One. 2013;8(4, article e62168)
    1. Strüh C. M., Jäger S., Schempp C. M., Scheffler A., Martin S. F. A novel triterpene extract from mistletoe induces rapid apoptosis in murine B16.F10 melanoma cells. Phytotherapy Research. 2012;26(10):1507–1512. doi: 10.1002/ptr.4604.
    1. Gloger O., Witthohn K., Muller B. W. Lyoprotection of aviscumine with low molecular weight dextrans. International Journal of Pharmaceutics. 2003;260(1):59–68. doi: 10.1016/S0378-5173(03)00234-5.
    1. Webb J. Enzyme and Metabolic Inhibitors. New York: Academic Press; 1963. Effect of more than one inhibitor; pp. 66–79. (488–512)
    1. Janssen O., Scheffler A., Kabelitz D. In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis) Arzneimittel-Forschung. 1993;43(11):1221–1227.
    1. Schaffrath B., Mengs U., Schwarz T., et al. Anticancer activity of rViscumin (recombinant mistletoe lectin) in tumor colonization models with immunocompetent mice. Anticancer Research. 2001;21(6a):3981–3987.
    1. Pratheeshkumar P., Kuttan G. Oleanolic acid induces apoptosis by modulating p53, Bax, Bcl-2 and caspase-3 gene expression and regulates the activation of transcription factors and cytokine profile in B16F. Journal of Environmental Pathology, Toxicology and Oncology. 2011;30(1):21–31. doi: 10.1615/JEnvironPatholToxicolOncol.v30.i1.30.
    1. Ji H. F., Li X. J., Zhang H. Y. Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Reports. 2009;10(3):194–200. doi: 10.1038/embor.2009.12.
    1. Gilbert B., Alves L. F. Synergy in plant medicines. Current Medicinal Chemistry. 2003;10(1):13–20. doi: 10.2174/0929867033368583.
    1. Williamson E. M. Synergy and other interactions in phytomedicines. Phytomedicine. 2001;8(5):401–409. doi: 10.1078/0944-7113-00060.
    1. Bantel H., Engels I. H., Voelter W., Schulze-Osthoff K., Wesselborg S. Mistletoe lectin activates caspase-8/FLICE independently of death receptor signaling and enhances anticancer drug-induced apoptosis. Cancer Research. 1999;59(9):2083–2090.
    1. Khil L. Y., Kim W., Lyu S., Park W. B., Yoon J. W., Jun H. S. Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells. World Journal of Gastroenterology. 2007;13(20):2811–2818.
    1. Ito Y., Pandey P., Place A., et al. The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism. Cell Growth & Differentiation. 2000;11(5):261–267.
    1. Ito Y., Pandey P., Sporn M. B., Datta R., Kharbanda S., Kufe D. The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Molecular Pharmacology. 2001;59(5):1094–1099.
    1. Samudio I., Kurinna S., Ruvolo P., et al. Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells. Molecular Cancer Therapeutics. 2008;7(5):1130–1139. doi: 10.1158/1535-7163.MCT-07-0553.
    1. Petronelli A., Saulle E., Pasquini L., et al. High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide. Cancer Letters. 2009;282(2):214–228. doi: 10.1016/j.canlet.2009.03.018.
    1. He X., Wang Y., Hu H., Zhang Z. In vitro and in vivo antimammary tumor activities and mechanisms of the apple total triterpenoids. Journal of Agricultural and Food Chemistry. 2012;60(37):9430–9436. doi: 10.1021/jf3026925.
    1. Yoo K. H., Park J. H., Cui E. J., et al. 3-O-acetyloleanolic acid induces apoptosis in human colon carcinoma HCT-116 cells. Phytotherapy Research. 2012;26(10):1541–1546. doi: 10.1002/ptr.4616.
    1. Eichenmüller M., Hemmerlein B., von Schweinitz D., Kappler R. Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma. British Journal of Cancer. 2010;103(1):43–51. doi: 10.1038/sj.bjc.6605715.
    1. Fulda S., Friesen C., Los M., et al. Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Research. 1997;57(21):4956–4964.
    1. Samudio I., Konopleva M., Pelicano H., et al. A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis. Molecular Pharmacology. 2006;69(4):1182–1193. doi: 10.1124/mol.105.018051.
    1. Konopleva M., Tsao T., Estrov Z., et al. The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Research. 2004;64(21):7927–7935. doi: 10.1158/0008-5472.CAN-03-2402.
    1. Park S. J., Wu C. H., Gordon J. D., Zhong X., Emami A., Safa A. R. Taxol induces caspase-10-dependent apoptosis. The Journal of Biological Chemistry. 2004;279(49):51057–51067. doi: 10.1074/jbc.M406543200.
    1. Lee H. J., Pyo J. O., Oh Y., et al. AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. Nature Cell Biology. 2007;9(11):1303–1310. doi: 10.1038/ncb1650.
    1. Kang N., Cao S. J., Zhou Y., et al. Inhibition of caspase-9 by oridonin, a diterpenoid isolated from Rabdosia rubescens, augments apoptosis in human laryngeal cancer cells. International Journal of Oncology. 2015;47(6):2045–2056. doi: 10.3892/ijo.2015.3186.
    1. Jeong H. S., Choi H. Y., Lee E. R., et al. Involvement of caspase-9 in autophagy-mediated cell survival pathway. Biochimica et Biophysica Acta. 2011;1813(1):80–90. doi: 10.1016/j.bbamcr.2010.09.016.
    1. Gyrd-Hansen M., Farkas T., Fehrenbacher N., et al. Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Molecular and Cellular Biology. 2006;26(21):7880–7891. doi: 10.1128/MCB.00716-06.
    1. McDonnell M. A., Wang D., Khan S. M., Vander Heiden M. G., Kelekar A. Caspase-9 is activated in a cytochrome c-independent manner early during TNF|[alpha]|-induced apoptosis in murine cells. Cell Death & Differentiation. 2003;10(9):1005–1015. doi: 10.1038/sj.cdd.4401271.
    1. Zou W., Liu X., Yue P., et al. C-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-Cyano-3,12-Dioxooleana-1, 9-Dien-28-Oate in human lung cancer cells. Cancer Research. 2004;64(20):7570–7578. doi: 10.1158/0008-5472.CAN-04-1238.
    1. Fulda S. Molecular targeted therapies for rhabdomyosarcoma: focus on hedgehog and apoptosis signaling. Klinische Pädiatrie. 2013;225(3):115–119. doi: 10.1055/s-0032-1331762.
    1. Gao X., Liu Y., Deeb D., et al. ROS mediate proapoptotic and antisurvival activity of oleanane triterpenoid CDDO-me in ovarian cancer cells. Anticancer Research. 2013;33(1):215–221.
    1. Shishodia S., Sethi G., Konopleva M., Andreeff M., Aggarwal B. B. A synthetic triterpenoid, CDDO-me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clinical Cancer Research. 2006;12(6):1828–1838. doi: 10.1158/1078-0432.CCR-05-2044.
    1. Fulda S. Cell death pathways as therapeutic targets in rhabdomyosarcoma. Sarcoma. 2012;2012:5. doi: 10.1155/2012/326210.326210
    1. Lavastre V., Pelletier M., Saller R., Hostanska K., Girard D. Mechanisms involved in spontaneous and Viscum album agglutinin-I-induced human neutrophil apoptosis: Viscum album agglutinin-I accelerates the loss of antiapoptotic mcl-1 expression and the degradation of cytoskeletal paxillin and vimentin proteins via caspases. Journal of Immunology. 2002;168(3):1419–1427.
    1. Ryu K., Susa M., Choy E., et al. Oleanane triterpenoid CDDO-me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer. 2010;10(1):p. 187.
    1. Fangusaro J. R., Caldas H., Jiang Y., Altura R. A. Survivin: an inhibitor of apoptosis in pediatric cancer. Pediatric Blood & Cancer. 2006;47(1):4–13. doi: 10.1002/pbc.20805.
    1. Koff J. L., Ramachandiran S., Bernal-Mizrachi L. A time to kill: targeting apoptosis in cancer. International Journal of Molecular Sciences. 2015;16(2):2942–2955. doi: 10.3390/ijms16022942.
    1. Caldas H., Holloway M. P., Hall B. M., Qualman S. J., Altura R. A. Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo. Journal of Medical Genetics. 2006;43(2):119–128. doi: 10.1136/jmg.2005.034686.
    1. Lúcio K. A., Rocha Gda G., Monção-Ribeiro L. C., Fernandes J., Takiya C. M., Gattass C. R. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PloS One. 2011;6(12, article e28596)
    1. Duan Z., Ames R. Y., Ryan M., Hornicek F. J., Mankin H., Seiden M. V. CDDO-me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemotherapy and Pharmacology. 2009;63(4):681–689. doi: 10.1007/s00280-008-0785-8.
    1. Shyu M. H., Kao T. C., Yen G. C. Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. Journal of Agricultural and Food Chemistry. 2010;58(10):6110–6118. doi: 10.1021/jf100574j.
    1. Elluru S., Duong Van Huyen J. P., Delignat S., et al. Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador. Arzneimittel-Forschung. 2006;56(6a):461–466.
    1. Hajtó T., Fodor K., Perjési P., Németh P. Difficulties and perspectives of immunomodulatory therapy with mistletoe lectins and standardized mistletoe extracts in evidence-based medicine. Evidence-Based Complementary and Alternative Medicine. 2011;2011:6. doi: 10.1093/ecam/nep191.298972

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj