Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells
Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92.1.7 cells without evident autophagy. The autophagy of K562 cells induced by AM involved autophagic flux, including autophagosome induction, the processing of autophagosome-lysosome fusion and downregulation of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). By bcr-abl knockdown, the growth inhibition of K562 cells caused by AM was partially blocked, suggesting that AM-induced cell death might be a bcr-abl-dependent mode of autophagy-associated cell death. In conclusion, AM is capable of inhibiting growth and inducing autophagy-associated cell death in K562 cells, but not in normal monocytes. It may have potential to be developed as a novel therapeutic agent against leukemia.
KeywordsArmillaridin Autophagy bcr-abl BNIP3 Chronic myelogenous leukemia
BCL2/adenovirus E1B 19 kDa interacting protein 3
Chronic myelogenous leukemia
Signal transduction inhibitor-571
We want to thank Dr. King-Song Jeng and the National RNAi Core Facility, Academia Sinica, Taiwan, for shRNA knockdown techniques, the pTRC-905 vector, and the pTRC-905-shBCR constructions. This work was supported by grant NSC98-2323-B-241 from the National Science Council, Taiwan, and grant 09MMHIS027 and MMH-E-105-13, E-104-13 from MacKay Memorial Hospital, Taiwan.
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Conflicts of interest
- 2.Apperley JF. Chronic myeloid leukaemia. Lancet. 2014.Google Scholar
- 3.Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, Galavotti S, Young KW, Selmi T, Yacobi R, Van Etten RA, Donato N, Hunter A, Dinsdale D, Tirro E, Vigneri P, Nicotera P, Dyer MJ, Holyoake T, Salomoni P, Calabretta B. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest. 2009;119:1109–23.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Chi CW, Chen CC, Chen YJ. Therapeutic and radiosensitizing effects of armillaridin on human esophageal cancer cells. Evidence-based complementary and alternative medicine: eCAM. 2013;2013:459271.Google Scholar
- 9.Strober W. Trypan blue exclusion test of cell viability. Current protocols in immunology/edited by John E Coligan [et al]. 2001;Appendix 3:Appendix 3B.Google Scholar