Immunomodulatory Activity and Inhibitory Effects of Viscum album on Cancer Cells, Its Safety Profiles and Recent Nanotechnology Development

Abstract

Viscum album has been employed traditionally to treat various ailments including as add-on therapy for cancer treatment. V. album formulations have been employed as adjuvants in cancer treatment due to their immunomodulatory activities as well as to alleviate the side effects of conventional cancer therapies. The present review provides updated information from the past 10 years on the immunomodulatory activity and inhibitory effects of V. album on cancer cells, its safety profile, and recent nanotechnology development. V. album extracts and their bioactive phytochemicals, particularly lectins, viscotoxins, and polyphenols, have demonstrated immunomodulatory activity and inhibitory effects against various types of cancer, with low cytotoxicity and side effects, in experimental studies and demonstrated promising anticancer activity in clinical studies in cancer patients. V. album extracts have been shown to enhance immune function by promoting cytokine secretion and inducing both innate and adaptive immune responses, which can help improve immune surveillance against cancer cells. The development of V. album nanoparticles has boosted their biological activities, including inhibitory activity on cancer cells, and could possibly reduce undesired side effects of the plant. Further prospective studies on the plant as a source of new medicinal agents for use as an adjuvant in the treatment of cancer must be performed to provide sufficient efficacy and safety data.

Keywords

Viscum album - Santalaceae - immunomodulation - anticancer effects - safety profiles - nanoparticles

Publikationsverlauf

Eingereicht: 04. April 2024

Angenommen nach Revision: 23. August 2024

Artikel online veröffentlicht:
23. September 2024

• References

• 1 Iannello A, Thompson TW, Ardolino M, Marcus A, Raulet DH. Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr Opin Immunol 2016; 38: 52-58
• 2 Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells – Mechanisms of immune surveillance and escape. Nat Rev Clin Oncol 2017; 14: 155-167
• 3 Lisiecka U, Kostro K. Mechanisms of tumour escape from immune surveillance. J Vet Res 2016; 60: 453-460
• 4 Oei SL, Thronicke A, Kröz M, Matthes H, Schad F. Use and safety of Viscum album L applications in cancer patients with preexisting autoimmune diseases: Findings from the network oncology study. Integr Cancer Ther 2019; 18: 1534735419832367
• 5 Mohamed SIA, Jantan I, Haque MA. Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action. Int Immunopharmacol 2017; 50: 291-304
• 6 Menke K, Schwermer M, Schramm A, Zuzak TJ. Preclinical evaluation of antitumoral and cytotoxic properties of Viscum album fraxini extract on pediatric tumor cells. Planta Med 2019; 85: 1150-1159
• 7 Szurpnicka A, Wrońska AK, Bus K, Kozińska A, Jabłczyńska R, Szterk A, Lubelska K. Phytochemical screening and effect of Viscum album L. on monoamine oxidase A and B activity and serotonin, dopamine and serotonin receptor 5-HTR1A levels in Galleria mellonealla (Lepidoptera). J Ethnopharmacol 2022; 298: 115604
• 8 Kienle GS, Mussler M, Fuchs D, Kiene H. Intravenous mistletoe treatment in integrative cancer care: a qualitative study exploring the procedures, concepts, and observations of expert doctors. Evid Based Complement Alternat Med 2016; 2016: 4628287
• 9 Elluru S, Van Huyen JPD, Delignat S, Prost F, Bayry J, Kazatchkine MD, Kaveri SV. Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador. Arzneimittelforschung 2006; 56: 461-466
• 10 Kienle GS, Kiene H. Complementary cancer therapy: A systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res 2007; 12: 103
• 11 Horneber M, van Ackeren G, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev 2008; (02) CD003297
• 12 Kröz M, Kienle GS, Feder G, Kaveri S, Rosenzweig S. Mistletoe: from basic research to clinical outcomes in cancer and other indications. Evid Based Complement Alternat Med 2014; 2014: 987527
• 13 Bonamin LV, De Carvalho AC, Waisse S. Viscum album (L.) in experimental animal tumors: A meta-analysis. Exp Ther Med 2017; 13: 2723-2740
• 14 Oei SL, Thronicke A, Schad F, An HJ. Mistletoe and immunomodulation: Insights and implications for anticancer therapies. Evid Based Complement Alternat Med 2019; 2019: 5893017
• 15 Thronicke A, Schad F, Debus M, Grabowski J, Soldner G. Viscum album L. therapy in oncology: An update on current evidence. Complement Med Res 2022; 29: 362-368
• 16 Baltazar T, Pejchal M, Varga I. Modelling of the distribution of European mistletoe (Viscum album) with dependence on local factors in the Castle Park in Lednice. Acta Univ Agric Silvic Mendel Brun 2015; 63: 1441-1452
• 17 Maul K, Krug M, Nickrent DL, Müller KF, Quandt D, Wicke S. Morphology, geographic distribution, and host preferences are poor predictors of phylogenetic relatedness in the mistletoe genus Viscum L. Mol Phylogenet Evol 2019; 131: 106-115
• 18 Walas Ł, Kędziora W, Ksepko M, Rabska M, Tomaszewski D, Thomas PA, Wójcik R, Iszkuło G. The future of Viscum album L. in Europe will be shaped by temperature and host availability. Sci Rep 2022; 12: 17072
• 19 García-García JD, Anguiano-Cabello JC, Arredondo-Valdés R, Candido del Toro CA, Martínez-Hernández JL, Segura-Ceniceros EP, Govea-Salas M, González-Chávez ML, Ramos-González R, Esparza-González SC, Ascacio-Valdés JA, López-Badillo CM, Ilyina A. Phytochemical characterization of Phoradendron bollanum and Viscum album subs. austriacum as Mexican mistletoe plants with antimicrobial activity. Plants 2021; 10: 1299
• 20 Nicoletti M. The antioxidant activity of mistletoes (Viscum album and other species). Plants 2023; 12: 2707
• 21 de Almeida VP, Monchak IT, da Costa Batista JV, Grazi M, Ramm H, Raman V, Baumgartner S, Holandino C, Manfron J. Investigations on the morpho-anatomy and histochemistry of the European mistletoe: Viscum album L. subsp. album . Sci Rep 2023; 13: 4604
• 22 Panossian A, Kocharian A, Matinian K, Amroyan E, Gabrielian E, Mayr C, Wagner H. Pharmacological activity of phenylpropanoids of the mistletoe, Viscum album L., host: Pyrus caucasica Fed. Phytomedicine 1998; 5: 11-17
• 23 Skidmore-Roth L. Mosbyʼs Handbook of Herbs and Natural Supplements. St Louis, MO: Mosby; 2004: 663
• 24 Nazaruk J, Orlikowski P. Phytochemical profile and therapeutic potential of Viscum album L. Nat Prod Res 2016; 30: 373-385
• 25 Ullah M, Mehmood S, Khan RA, Ali M, Fozia F, Waqas M, Ullah R, Alotaibi A, Sultan MA. Assessment of antidiabetic potential and phytochemical profiling of Viscum album, a traditional antidiabetic plant. J Food Qual 2022; 2022: 5691379
• 26 Holandino C, Melo MNO, Oliveira AP, Batista JVDC, Capella MAM, Garrett R, Grazi M, Ramm H, Torre CD, Schaller G, Urech K, Weissenstein U, Baumgartner S. Phytochemical analysis and in vitro anti-proliferative activity of Viscum album ethanolic extracts. BMC Complement Med Ther 2020; 20: 215
• 27 Gupta G, Kazmi I, Afzal M, Rahman M, Saleem S, Ashraf MS, Khusroo MJ, Nazeer K, Ahmed S, Mujeeb M, Ahmed Z. Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. J Ethnopharmacol 2012; 141: 810-816
• 28 Segneanu AE, Marin CN, Herea DD, Stanusoiu I, Muntean C, Grozescu I. Romanian Viscum album L. – Untargeted low-molecular metabolomic approach to engineered viscum–AuNPs carrier assembly. Plants 2022; 11: 1820
• 29 Singh BN, Saha C, Galun D, Upreti DK, Bayry J, Kaveri SV. European Viscum album: A potent phytotherapeutic agent with multifarious phytochemicals, pharmacological properties and clinical evidence. RSC Adv 2016; 6: 23837-23857
• 30 Martin Cordero C, Gil Serrano AM, Ayuso Gonzalez MJ. Transfer of bipiperidyl and quinolizidine alkaloids to Viscum cruciatum Sieber (Loranthaceae) hemiparasitic on Retama sphaerocarpa Boissier (Leguminosae). J Chem Ecol 1993; 19: 2389-2393
• 31 Wójciak-Kosior M, Sowa I, Pucek K, Szymczak G, Kocjan R, Luchowski P. Evaluation of seasonal changes of triterpenic acid contents in Viscum album from different host trees. Pharm Biol 2017; 55: 1-4
• 32 Melo MNDO, Ochioni AC, Zancan P, Oliveira AP, Garrett R, Holandino C, Baumgartner S. Viscum album mother tinctures: Harvest conditions and host trees influence the plant metabolome and the glycolytic pathway of breast cancer cells. Front Pharmacol 2022; 13: 1027931
• 33 Jäger T, Holandino C, Melo MN, Peñaloza EM, Oliveira AP, Garrett R, Glauser G, Grazi M, Ramm H, Urech K, Baumgartner S. Metabolomics by UHPLC-Q-TOF reveals host tree-dependent phytochemical variation in Viscum album L. Plants 2021; 10: 1726-1738
• 34 Moyo B, Tavengwa NT, Madala NE. Application of the UHPLC-q-TOF-MS and molecular networking in revealing chemo-taxonomical markers of Viscum combreticola Engl. and Viscum album L. Biochem Syst Ecol 2023; 111: 104720-104728
• 35 Lyu SY, Park WB. Mistletoe lectin (Viscum album coloratum) modulates proliferation and cytokine expressions in murine splenocytes. BMB Rep 2006; 39: 662-670
• 36 Majeed M, Hakeem KR, Rehman RU. Mistletoe lectins: From interconnecting proteins to potential tumour inhibiting agents. Phytomed Plus 2021; 1: 100039-100047
• 37 Yousefvand S, Fattahi F, Hosseini SM, Urech K, Schaller G. Viscotoxin and lectin content in foliage and fruit of Viscum album L. on the main host trees of Hyrcanian forests. Sci Rep 2022; 12: 10383
• 38 Majeed M, Rehman RU. Phytochemistry, Pharmacology, and Toxicity of an Epiphytic Medicinal Shrub Viscum album L. (white Berry Mistletoe). In: Aftab T, Hakeem KR. editors Medicinal and Aromatic Plants: Healthcare and Industrial Applications. Cham: Springer; 2021: 287-301
• 39 Ahmad MS, Rasheed S, Falke S, Khaliq B, Perbandt M, Choudhary MI, Markiewicz WT, Barciszewski J, Betzel C. Crystal structure of mistletoe lectin I (ML-I) from Viscum album in complex with 4-N-furfurylcytosine at 2.85 Å resolution. Med Chem 2018; 14: 754-763
• 40 Saha C, Hegde P, Friboulet A, Bayry J, Kaveri SV. Viscum album-mediated COX-2 inhibition implicates destabilization of COX-2 mRNA. PLoS One 2015; 10: e0114965
• 41 Burdějová L, Moravcová D, Strouhalová D, Lunerová K. Pressurized water extraction–the fast and efficient method for isolation of bioactive proteins from Viscum album leaves. J Pharm Biomed Anal 2021; 195: 113850-113856
• 42 Stefanucci A, Zengin G, Llorent-Martinez EJ, Dimmito MP, Della Valle A, Pieretti S, Ak G, Sinan KI, Mollica A. Viscum album L. homogenizer‐assisted and ultrasound‐assisted extracts as potential sources of bioactive compounds. J Food Biochem 2020; 44: e13377-e13389
• 43 Kleszken E, Timar AV, Memete AR, Miere F, Vicas SI. On overview of bioactive compounds, biological and pharmacological effects of mistletoe (Viscum album L). Pharmacophore 2022; 13: 10-26
• 44 Dai JK, Cao D, Li CH, Gao J, Li MQ, Fan N, Wei YH, Sun ZL, Hou MY. Three new bioactive flavonoid glycosides from Viscum album . Chin J Nat Med 2019; 17: 545-550
• 45 Su GZ, Wang SY, Yang XY, Stevanović ZD, Li N, Tanić N, Arsenijević N, Yu SS, Li Y. Dihydroflavonoid glycosides from Viscum album and their inhibitory effects on hepatic lipid accumulation and target identification. Phytochemistry 2022; 204: 113458
• 46 Pietrzak W, Nowak R. Impact of harvest conditions and host tree species on chemical composition and antioxidant activity of extracts from Viscum album L. Molecules 2021; 26: 3741
• 47 Kleszken E, Purcarea C, Pallag A, Ranga F, Memete AR, Miere F, Vicas SI. Phytochemical profile and antioxidant capacity of Viscum album L. Subsp. album and effects on its host trees. Plants 2022; 11: 3021
• 48 de Oliveira Melo MN, Oliveira AP, Wiecikowski AF, Carvalho RS, de Lima Castro J, de Oliveira FA, Pereira HM, da Veiga VF, Capella MM, Rocha L, Holandino C. Studies on the constituents of the European mistletoe, Viscum album L. Chem Pharm Bull 1987; 35: 3292-3297
• 49 Fukunaga T, Kajikawa I, Nishiya K, Watanabe Y, Takeya K, Itokawa H. Studies on the constituents of the European mistletoe, Viscum album L. Chem Pharm Bull 1987; 35: 3292-3297
• 50 Fukunaga T, Kajikawa I, Nishiya K, Watanabe Y, Suzuki N, Takeya K, Itokawa H. Studies on the constituents of the European mistletoe, Viscum album L. II. Chem Pharm Bull 1988; 36: 1185-1189
• 51 Soursouri A, Hosseini SM, Fattahi F. Seasonal variations of triterpene acid contents in Viscum album L. on typical host trees of Hyrcanian forests. Sci Rep 2023; 13: 11587
• 52 Cao D, Wang LQ, Han XM, Guan HR, Lei M, Wei YH, Cheng L, Yang PM, Sun ZL, Gao W, Dai JK. Two symmetrical unsaturated acids isolated from Viscum album . Chin J Nat Med 2019; 17: 145-148
• 53 Kürkçüoğlu M, Başer K, Demirci B, Orhan DD, Ergün F. Composition of the essential oils of Viscum album L. subspecies from Turkey. Gazi Universitesi Eczacilik Fakultesi Dergisi 2002; 19: 87-92
• 54 Geraci A, Schicchi R, Sgadari F, Badalamenti N, Bruno M. The essential oil compositions of three Sicilian accessions of Viscum album L. growing on three different host trees. Nat Prod Res 2023; 37: 2623-2627
• 55 Kim CW, An CH, Lee HS, Yi JS, Cheong EJ, Lim SH, Kim HY. Proximate and mineral components of Viscum album var. coloratum grown on eight different host tree species. J For Res 2019; 30: 1245-1253
• 56 Zhou X, Zeng M, Huang F, Qin G, Song Z, Liu F. The potential role of plant secondary metabolites on antifungal and immunomodulatory effect. Appl Microbiol Biotechnol 2023; 107: 4471-4492
• 57 Burkard M, Leischner C, Lauer UM, Busch C, Venturelli S, Frank J. Dietary flavonoids and modulation of natural killer cells: Implications in malignant and viral diseases. J Nutr Biochem 2017; 46: 1-2
• 58 Ali Reza AS, Nasrin MS, Hossen MA, Rahman MA, Jantan I, Haque MA, Sobarzo-Sánchez E. Mechanistic insight into immunomodulatory effects of food-functioned plant secondary metabolites. Crit Rev Food Sci Nutr 2023; 63: 5546-5576
• 59 Cháirez-Ramírez MH, de la Cruz-López KG, García-Carrancá A. Polyphenols as antitumor agents targeting key players in cancer-driving signaling pathways. Front Pharmacol 2021; 12: 710304
• 60 Cuevas-Cianca SI, Romero-Castillo C, Gálvez-Romero JL, Juárez ZN, Hernández LR. Antioxidant and anti-inflammatory compounds from edible plants with anti-cancer activity and their potential use as drugs. Molecules 2023; 28: 1488
• 61 Ramakrishna W, Kumari A, Rahman N, Mandave P. Anticancer activities of plant secondary metabolites: Rice callus suspension culture as a new paradigm. Rice Sci 2021; 28: 13-30
• 62 Pop S, Enciu AM, Tarcomnicu I, Gille E, Tanase C. Phytochemicals in cancer prevention: Modulating epigenetic alterations of DNA methylation. Phytochem Rev 2019; 18: 1005-1024
• 63 Zubair H, Khan MA, Anand S, Srivastava SK, Singh S, Singh AP. Modulation of the tumor microenvironment by natural agents: Implications for cancer prevention and therapy. Semin Cancer Biol 2022; 80: 237-255
• 64 Kim YS, Kim SK, Park SJ. Apoptotic effect of demethoxyfumitremorgin C from marine fungus Aspergillus fumigatus on PC3 human prostate cancer cells. Chem Biol Interact 2017; 269: 18-24
• 65 Shoshan-Barmatz V, Arif T, Shteinfer-Kuzmine A. Apoptotic proteins with non-apoptotic activity: Expression and function in cancer. Apoptosis 2023; 28: 730-753
• 66 Łukasik P, Baranowska-Bosiacka I, Kulczycka K, Gutowska I. Inhibitors of cyclin-dependent kinases: Types and their mechanism of action. Int J Mol Sci 2021; 22: 2806
• 67 Ghanbari-Movahed M, Kaceli T, Mondal A, Farzaei MH, Bishayee A. Recent advances in improved anticancer efficacies of camptothecin nano-formulations: A systematic review. Biomedicines 2021; 9: 480
• 68 Fu Y, Li X, Yuan X, Zhang Z, Wei W, Xu C, Song J, Gu C. Alternaria alternata F3, a novel taxol-producing endophytic fungus isolated from the fruits of Taxus cuspidata: Isolation, characterization, taxol yield improvement, and antitumor activity. Appl Biochem Biotechnol 2024; 196: 2246-2269
• 69 Tomeh M, Hadianamrei R, Zhao X. A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci 2019; 20: 1033
• 70 Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WF, Shen HM, Wang J. Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Med Res Rev 2017; 37: 1492-1517
• 71 Akter Z, Ahmed FR, Tania M, Khan MA. Targeting inflammatory mediators: An anticancer mechanism of thymoquinone action. Curr Med Chem 2021; 28: 80-92
• 72 Melo MN, Batista JV, Peñaloza EM, Oliveira AP, Garrett R, Baumgartner S, Holandino C. A scoping review of genus Viscum: biological and chemical aspects of alcoholic extracts. Plants 2023; 12: 1811
• 73 Steinborn C, Klemd AM, Sanchez-Campillo AS, Rieger S, Scheffen M, Sauer B, Garcia-Käufer M, Urech K, Follo M, Ücker A, Kienle GS. Viscum album neutralizes tumor-induced immunosuppression in a human in vitro cell model. PLoS One 2017; 12: e0181553
• 74 Elluru SR, Saha C, Hedge P, Friboulet A, Bayry J, Kaveri SV. Dissecting the anti-inflammatory effects of Viscum album: Inhibition of cytokine-induced expression of cyclo-oxygenase-2 and secretion of prostaglandin E2. In: Mistletoe: From Mythology to Evidence-Based Medicine Basel: Karger; 2015. 4. 67-73
• 75 Murthuza S, Manjunatha BK. In vitro and in vivo evaluation of anti-inflammatory potency of Mesua ferrea, Saraca asoca, Viscum album & Anthocephalus cadamba in murine macrophages raw 264.7 cell lines and Wistar albino rats. Beni-Suef Univ J Basic Appl Sci 2018; 7: 719-723
• 76 Ha SM, Kim JH, Kim JW, Kim DY, Ha MS. The potential role of Korean mistletoe extract as an anti-inflammatory supplementation. J Immunol Res 2021; 2021: 2183427
• 77 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
• 78 Goldar S, Khaniani MS, Derakhshan SM, Baradaran B. Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac J Cancer Prev 2015; 16: 2129-2144
• 79 Süntar I. Importance of ethnopharmacological studies in drug discovery: Role of medicinal plants. Phytochem Rev 2020; 19: 1199-1209
• 80 Szurpnicka A, Kowalczuk A, Szterk A. Biological activity of mistletoe: in vitro and in vivo studies and Mechanisms of action. Arch Pharm Res 2020; 43: 593-629
• 81 Freuding M, Keinki C, Micke O, Buentzel J, Huebner J. Mistletoe in oncological treatment: a systematic review: Part 1: survival and safety. J Cancer Res Clin Oncol 2019; 145: 695-707
• 82 Reynel M, Villegas Y, Kiene H, Werthmann PG, Kienle GS. In-vitro growth kinetics of mesenchymal stem cells in cytotoxicity tests using low-diluted Viscum album . Homeopathy 2023; 112: 040-049
• 83 Valle AC, Brunel HD, Dallago BS, Rodrigues LS, Malard PF, da Costa RA, Rossetto R, de Andrade RV. In-vitro growth kinetics of mesenchymal stem cells in cytotoxicity tests using low-diluted Viscum album . Homeopathy 2023; 112: 040-049
• 84 Yirgu A, Mekonnen Y, Eyado A, Staropoli A, Vinale F. Biological activities of Viscum tuberculatum aqueous leaf extract. Pharm Biol 2023; 61: 30-36
• 85 Farooqi AA, Sabitaliyevich UY. How far we have gone in realizing true potential of Viscum album as versatile regulator of cell signaling pathways. Cell Mol Biol 2019; 65: 1-2
• 86 Park YR, Jee W, Park SM, Kim SW, Bae H, Jung JH, Kim H, Kim S, Chung JS, Jang HJ. Viscum album induces apoptosis by regulating STAT3 signaling pathway in breast cancer cells. Int J Mol Sci 2023; 24: 11988
• 87 Choi HJ, Park SJ, Choi YN, Kim SD, Kwag EB, Song SY, Park JH, Kim JK, Seo C, Choi JJ, Yoo HS. Selective immune modulating activities of Viscum album and its components; a possibility of therapeutics on skin rash induced by EGFR inhibitors. Integr Cancer Ther 2022; 21
• 88 Han SY, Hong CE, Kim HG, Lyu SY. Anti-cancer effects of enteric-coated polymers containing mistletoe lectin in murine melanoma cells in vitro and in vivo . Mol Cell Biochem 2015; 408: 73-87
• 89 Weissenstein U, Kunz M, Urech K, Regueiro U, Baumgartner S. Interaction of a standardized mistletoe (Viscum album) preparation with antitumor effects of Trastuzumab in vitro . BMC Complement Altern Med 2016; 16: 1-10
• 90 Harati K, Behr B, Daigeler A, Hirsch T, Jacobsen F, Renner M, Harati A, Wallner C, Lehnhardt M, Becerikli M. Curcumin and Viscum album extract decrease proliferation and cell viability of soft-tissue sarcoma cells: an in vitro analysis of eight cell lines using real-time monitoring and colorimetric assays. Nutr Cancer 2017; 69: 340-351
• 91 dela Cruz JF, Kim YS, Lumbera WM, Hwang SG. Viscum album var hot water extract mediates anti-cancer effects through G1 phase cell cycle arrest in SK-Hep1 human hepatocarcinoma cells. Asian Pac J Cancer Prev 2015; 16: 6417-6421
• 92 Schötterl S, Miemietz JT, Ilina EI, Wirsik NM, Ehrlich I, Gall A, Huber SM, Lentzen H, Mittelbronn M, Naumann U. Mistletoe-based drugs work in synergy with radio-chemotherapy in the treatment of glioma in vitro and in vivo in glioblastoma bearing mice. Evid Based Complement Alternat Med 2019; 2019: 1376140
• 93 Valle AC, Aguiar LR, Brunel HD, Malard PF, Villarroel CL, Andrade RV. Homoeopathic Viscum album (10–3) is more cytotoxic to in vitro culture of human breast cancer cell line than to human mesenchymal stem cells. Int J High Dilution Res 2020; 19: 25-34
• 94 Batista JV, Matos AP, Oliveria AP, Ricci Júnior E, Freitas ZM, Oliveira CA, Toma HK, Capella MA, Rocha LM, Weissenstein U, Baumgartner S. Thermoresponsive hydrogel containing Viscum album extract for topic and transdermal use: development, stability and cytotoxicity activity. Pharmaceutics 202; 14: 37.
• 95 Wright A, Watanabe R, Koehler JW. European mistletoe (Viscum album) extract is cytotoxic to canine high-grade astrocytoma cells in vitro and has additive effects with mebendazole. Vet Sci 2022; 9: 31
• 96 Delebinski CI, Twardziok M, Kleinsimon S, Hoff F, Mulsow K, Rolff J, Jäger S, Eggert A, Seifert G. 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: e0133892
• 97 Çetin ES, Sozen H, Celik OI, Cigerci IH, Yılmaz N. Mistletoe (Viscum album L.) extract attenuates itraconazole-induced acute oxidative stress and hepatocellular injury in rats. Pak J Pharm Sci 2023; 36: 9-16
• 98 Milošević MD, Mašković PZ, Stanković VD, Paunović MG, Mitić MN, Matić MM, Ognjanović BI. Protective effects of Viscum album L. leaf extract on chlorpyrifos-induced hepatotoxicity in Wistar rats. J King Saud Univ-Sci 2022; 34: 101957
• 99 Yusuf L, Oladunmoye MK, Ogundare AO, Mohmo MO, Daudu OA. Comparative antifungal and toxicological effects of the extract of mistletoes growing on two different host plants in Akure North, Nigeria. Int J Biotech Food Sci 2014; 2: 31-34
• 100 Ghelman R, Cernach MC, de Souza Ishigai MM, Hosomi JK, de Jesus Simões M, Kulay jr. L, da Costa Batista JV, Delebinski C, Seifert G, Nakamura MU. The safety of Viscum album L. in a murine model: A reproductive toxicity study. Accessed 2024-04-04 at: http://www.researchsquare.com Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia.
• 101 Wasagwa J, Lawan BB, Abdullahi BA, Joshua L, Saidu NI, God OE. Phytochemistry and toxicity studies on aqueous extracts of leaf and stem of mistletoe (Viscum album) in albino rats. Int J Hom Sci 2018; 4: 1-5
• 102 Pelzer F, Tröger W. Complementary treatment with mistletoe extracts during chemotherapy: safety, neutropenia, fever, and quality of life assessed in a randomized study. J Altern Complement Med 2018; 24: 954-961
• 103 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. Eur J Cancer 2013; 49: 3788-3797
• 104 Longhi A, Reif M, Mariani E, Ferrari S. A randomized study on post relapse disease-free survival with adjuvant mistletoe versus oral etoposide in osteosarcoma patients. Evid Based Complement Alternat Med 2014; 2014: 210198
• 105 Bock PR, Friedel WE, Hanisch J, Karasmann M, Schneider B. [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma/results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland]. Arzneimittelforschung 2004; 54: 456-466
• 106 Huber R, Schlodder D, Effertz C, Rieger S, Tröger W. Safety of intravenously applied mistletoe extract–results from a phase I dose escalation study in patients with advanced cancer. BMC Complement Altern Med 2017; 17: 1-8
• 107 Steele ML, Axtner J, Happe A, Kröz M, Matthes H, Schad F. Safety of intravenous application of mistletoe (Viscum album L.) preparations in oncology: An observational study. Evid Based Complement Alternat Med 2014; 2014: 236310
• 108 Paller CJ, Wang L, Fu W, Kumar R, Durham JN, Azad NS, Laheru DA, Browner I, Kachhap SK, Boyapati K, Odeny T. Phase I trial of intravenous mistletoe extract in advanced cancer. Cancer Res Commun 2023; 3: 338-346
• 109 Büssing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (iscador): A meta-analysis. Evid Based Complement Alternat Med 2012; 2012: 219402
• 110 Wiebelitz KR, Beer AM. High dose intravenous mistletoe treatment-clinical results, laboratory findings and adverse events in a series of 17 patients with 107 intravenous applications. Phytomedicine 2011; 18: S11
• 111 Kim JD, Choi JW, Park HO, Lee CE, Jang IS, Choi JY, Kang DH, Jung JJ, Yang JH, Moon SH, Byun JH. Chemical pleurodesis with Viscum album L. extract for secondary spontaneous pneumothorax in elderly patients. J Thorac Dis 2020; 12: 5440
• 112 Thronicke A, Steele ML, Grah C, Matthes B, Schad F. Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer. BMC Complement Altern Med 2017; 17: 1-10
• 113 Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian J Chem 2019; 12: 908-931
• 114 Rajoriya P, Barcelos MC, Ferreira DC, Misra P, Molina G, Pelissari FM, Shukla PK, Ramteke PW. Green silver nanoparticles: Recent trends and technological developments. J Polym Environ 2021; 29: 2711-2737
• 115 Bhardwaj B, Singh P, Kumar A, Kumar S, Budhwar V. Eco-friendly greener synthesis of nanoparticles. Adv Pharm Bull 2020; 10: 566-576
• 116 Yosri N, Khalifa SA, Guo Z, Xu B, Zou X, El-Seedi HR. Marine organisms: Pioneer natural sources of polysaccharides/proteins for green synthesis of nanoparticles and their potential applications. Int J Biol Macromol 2021; 193: 1767-1798
• 117 Kashyap D, Tuli HS, Yerer MB, Sharma A, Sak K, Srivastava S, Pandey A, Garg VK, Sethi G, Bishayee A. Natural product-based nanoformulations for cancer therapy: Opportunities and challenges. Semin Cancer Biol 2021; 69: 5-23
• 118 Mushtaq W, Ishtiaq M, Maqbool M, Mazhar MW, Casini R, Abd-ElGawad AM, Elansary HO. Green synthesis of zinc oxide nanoparticles using Viscum album extracts: Unveiling bioactive compounds, antibacterial potential, and antioxidant activities. Plants (Basel) 2023; 12: 2130
• 119 Kokturk M, Yıldırım S, Atamanalp M, Calimli MH, Nas MS, Bolat I, Ozhan G, Alak G. Assessment of oxidative DNA damage, apoptosis and histopathological alterations on zebrafish exposed with green silver nanoparticle. Chem Ecol 2022; 38: 655-670
• 120 Flieger J, Franus W, Panek R, Szymańska-Chargot M, Flieger W, Flieger M, Kołodziej P. Green synthesis of silver nanoparticles using natural extracts with proven antioxidant activity. Molecules 2021; 26: 4986
• 121 Khalatbary M, Sayadi MH, Hajiani M, Nowrouzi M, Homaeigohar S. Green, sustainable synthesis of γ-Fe2O3/MWCNT/Ag nano-composites using the viscum album leaf extract and waste car tire for removal of sulfamethazine and bacteria from wastewater streams. Nanomaterials 2022; 12: 2798
• 122 Sayadi MH, Ghollasimood S, Ahmadpour N, Homaeigohar S. Biosynthesis of the ZnO/SnO2 nanoparticles and characterization of their photocatalytic potential for removal of organic water pollutants. J Photochem Photobiol A Chem 2022; 425: 113662
• 123 Fifere N, Airinei A, Doroftei F, Ardeleanu TS, Dobromir M, Tîmpu D, Ursu EL. Phytomediated-assisted preparation of cerium oxide nanoparticles using plant extracts and assessment of their structural and optical properties. Int J Mol Sci 2023; 24: 8917