Apoptosis of K562 leukemia cells by Abnobaviscum F®, a European mistletoe extract

Park,Yu-Kyoung; Do,Young  Rok; Jang,Byeong-Churl

doi:10.3892/or.2012.2026

Apoptosis of K562 leukemia cells by Abnobaviscum F®, a European mistletoe extract

Authors:
- Yu-Kyoung Park
- Young Rok Do
- Byeong-Churl Jang
View Affiliations

Affiliations: Department of Medical Genetic Engineering, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, Republic of Korea, Department of Hemato-Oncology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, Republic of Korea
Published online on: September 12, 2012 https://doi.org/10.3892/or.2012.2026
Pages: 2227-2232

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Evidence suggests that mistletoe extract has the potential to be used as an anticancer agent. Abnobaviscum F® is a European mistletoe extract from the host tree Fraxinus. We investigated the effect of Abnobaviscum F on the growth and survival of different leukemia cell lines. Abnobaviscum F treatment strongly reduced survival and induced apoptosis of K562 (human myeloid leukemia), RPMI-8226 (human plasmacytoma) and L1210 (murine lymphocytic leukemia) cells in culture. Using K562 cells to further investigate the mechanism of action of Abnobaviscum F, we showed that Abnobaviscum F-induced cell death was associated with the activation of caspase-9, JNK-1/2 and p38 MAPK, as well as with the downregulation of Mcl-1, and inhibition of ERK-1/2 and PKB phosphorylation. Moreover, Abnobaviscum F treatment led to both a reduction of cellular glutathione (GSH) and the induction of ER stress (GRP78 and CHOP induction and eIF-2α phosphorylation). By contrast, Abnobaviscum F did not impact the expression of the DR4 and DR5 death receptors. The Abnobaviscum F-induced apoptosis of K562 cells was blocked by pretreatment with either GSH, z-VAD-fmk or SP600125. Our results, therefore, show that Abnobaviscum F induces apoptosis of K562 cells through the activation of the intrinsic caspase pathway, the phosphorylation of JNK-1, the reduction of cellular GSH, and the induction of ER stress.

View Figures

View References

1	Borgaonkar DS: Philadelphia-chromosome translocation and chronic myeloid leukaemia. Lancet. 1:12501973. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Ward E, et al: Cancer statistics. CA Cancer J Clin. 59:225–249. 2009.
3	Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 344:1031–1037. 2001. View Article : Google Scholar : PubMed/NCBI
4	Druker BJ, Guilhot F, O’Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 355:2408–2417. 2006.PubMed/NCBI
5	Ernst E, Schmidt K and Steuer-Vogt MK: Mistletoe for cancer? A systematic review of randomised clinical trials. Int J Cancer. 107:262–267. 2003. View Article : Google Scholar : PubMed/NCBI
6	Khwaja TA, Dias CB and Pentecost S: Recent studies on the anticancer activities of mistletoe Viscum album and its alkaloids. Oncology. 1:42–50. 1986. View Article : Google Scholar : PubMed/NCBI
7	Urech K, Schaller G and Jaggy C: Viscotoxins, mistletoe lectins and their isoforms in mistletoe Viscum album L. extracts Iscador. Arzneimittelforschung. 56:428–434. 2006.PubMed/NCBI
8	Heinzerling L, von Baehr V, Liebenthal C, et al: Immunologic effector mechanisms of a standardized mistletoe extract on the function of human monocytes and lymphocytes in vitro, ex vivo, and in vivo. J Clin Immunol. 26:347–359. 2006. View Article : Google Scholar : PubMed/NCBI
9	Burger AM, Mengs U, Schüler JB, et al: Antiproliferative activity of an aqueous mistletoe extract in human tumor cell lines and xenografts in vitro. Arzneimittelforschung. 51:748–757. 2001.PubMed/NCBI
10	Büssing A, Suzart K and Schweizer K: Differences in the apoptosis-inducing properties of Viscum album L. extracts. Anticancer Drugs. 8:S9–S14. 1997.
11	Harmsma M, Ummelen M, Dignef W, et al: Effects of mistletoe Viscum album L. extracts Iscador on cell cycle and survival of tumor cells. Arzneimittelforschung. 56:474–482. 2006.
12	Kim MS, Lee J, Lee KM, et al: Involvement of hydrogen peroxide in mistletoe lectin-II-induced apoptosis of myeloleukemic U937 cells. Life Sci. 73:1231–1243. 2003. View Article : Google Scholar : PubMed/NCBI
13	Kim WH, Park WB, Gao B, et al: Critical role of reactive oxygen species and mitochondrial membrane potential in Korean mistletoe lectin-induced apoptosis in human hepatocarcinoma cells. Mol Pharmacol. 66:1383–1396. 2004. View Article : Google Scholar
14	Lyu SY, Park WB, Choi KH, et al: Involvement of caspase-3 in apoptosis induced by Viscum album varcoloratum agglutinin in HL-60 cells. Biosci Biotechnol Biochem. 65:534–541. 2001. View Article : Google Scholar : PubMed/NCBI
15	Kim MS, So HS, Lee KM, et al: Activation of caspase cascades in Korean mistletoe Viscum album var.coloratum lectin-II-induced apoptosis of human myeloleukemic U937 cells. Gen Pharmacol. 34:349–355. 2000.PubMed/NCBI
16	Lavastre V, Chiasson S, Cavalli H and Girard D: Viscum album agglutinin-I (VAA-I) induces apoptosis and degradation of cytoskeletal proteins in human leukemia PLB-985 and X-CGD cells via caspases: lamin B1 is a novel target of VAA-I. Leuk Res. 29:1443–1453. 2005. View Article : Google Scholar
17	Endo Y, Tsurugi K and Franz H: The site of action of the A-chain of mistletoe lectin I on eukaryotic ribosomes. The RNA N-glycosidase activity of the protein. FEBS Lett. 231:378–380. 1988. View Article : Google Scholar : PubMed/NCBI
18	Choi SH, Lyu SY and Park WB: Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res. 27:68–76. 2004. View Article : Google Scholar : PubMed/NCBI
19	Park R, Kim MS, So HS, et al: Activation of c-Jun N-terminal kinase 1 (JNK1) in mistletoe lectin II-induced apoptosis of human myeloleukemic U937 cells. Biochem Pharmacol. 60:1685–1691. 2000. View Article : Google Scholar
20	Pae HO, Oh GS, Kim NY, et al: Roles of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in apoptosis of human monoblastic leukemia U937 cells by lectin-II isolated from Korean mistletoe. In Vitr Mol Toxicol. 14:99–106. 2001. View Article : Google Scholar
21	Knöpfl-Sidler F, Viviani A, Rist L and Hensel A: Human cancer cells exhibit in vitro individual receptiveness towards different mistletoe extracts. Pharmazie. 60:448–454. 2005.PubMed/NCBI
22	Ribéreau-Gayon G, Jung ML, Di Scala D and Beck JP: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology. 43:35–41. 1986.PubMed/NCBI
23	Cohen GM: Caspase: the executioners of apoptosis. Biochem J. 326:1–16. 1997.
24	Lazebnik YA, Kaufmann SH, Desnoyers S, et al: Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 371:346–347. 1994. View Article : Google Scholar : PubMed/NCBI
25	Adams JM and Cory S: The Bcl-2 protein family: arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
26	Festjens N, Van Gurp M, Van Loo G, et al: Bcl-2 family members as sentinels of cellular intergrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol. 111:7–27. 2004. View Article : Google Scholar : PubMed/NCBI
27	Zhang B, Gojo I and Fenton RG: Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 99:1885–1893. 2002. View Article : Google Scholar : PubMed/NCBI
28	Yoeli-Lerner M and Toker A: Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle. 5:603–605. 2006. View Article : Google Scholar : PubMed/NCBI
29	Nakayama H, Ikebe T, Beppu M, et al: High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer. 92:3037–3044. 2001. View Article : Google Scholar : PubMed/NCBI
30	Kallergi G, Agelaki S, Kalykaki A, et al: Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients. Breast Cancer Res. 10:R802008. View Article : Google Scholar : PubMed/NCBI
31	Milella M, Kornblau SM, Estrov Z, et al: Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest. 108:851–859. 2001. View Article : Google Scholar : PubMed/NCBI
32	Lunghi P, Tabilio A, Dall’Aglio PP, et al: Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia. 17:1783–1793. 2003. View Article : Google Scholar : PubMed/NCBI
33	Tibbles LA and Woodgett JR: The stress-activated protein kinase pathways. Cell Mol Life Sci. 55:1230–1254. 1999. View Article : Google Scholar : PubMed/NCBI
34	Shim MJ, Kim HJ, Yang SJ, et al: Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. J Biochem Mol Biol. 35:377–383. 2002. View Article : Google Scholar : PubMed/NCBI
35	Takada E, Hata K and Mizuguchi J: c-Jun-NH2-terminal kinase potentiates apoptotic cell death in response to carboplatin in B lymphoma cells. Cancer Chemother Pharmacol. 62:569–576. 2008. View Article : Google Scholar : PubMed/NCBI
36	Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar : PubMed/NCBI
37	Nieto-Miguel T, Fonteriz RI, Vay L, et al: Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells. Cancer Res. 67:10368–10378. 2007. View Article : Google Scholar : PubMed/NCBI
38	Huang X, Zhang Z, Jia L, et al: Endoplasmic reticulum stress contributes to vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. Cancer Lett. 296:123–131. 2010. View Article : Google Scholar
39	Lee AS: The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci. 26:504–510. 2001. View Article : Google Scholar : PubMed/NCBI
40	Ma Y, Brewer JW, Diehl JA, et al: Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol. 318:1351–1365. 2002. View Article : Google Scholar : PubMed/NCBI
41	De Haro C, Méndez R and Santoyo J: The eIF-2alpha kinases and the control of protein synthesis. FASEB J. 10:1378–1387. 1996.PubMed/NCBI
42	Haze K, Yoshida H, Yanagi T, et al: Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 10:3787–3799. 1999. View Article : Google Scholar