Atromentin-Induced Apoptosis in Human Leukemia U937 Cells

  • Kim, Jin-Hee (Department of Bioscience and Biotechnology, Konkuk University) ;
  • Lee, Choong-Hwan (Department of Bioscience and Biotechnology, Konkuk University)
  • Published : 2009.09.30


In the course of screening for apoptotic substances that induce apoptosis in human leukemia U937 cells, a fungal strain, F000487, which exhibits potent inducible activity, was selected. The active compound was purified from an ethyl acetate extract of the microorganism by Sep-pak $C_{18}$ column chromatography and HPLC, and was identified as atromentin by spectroscopic methods. This compound induced caspase-3 processing in human leukemia U937 cells. The caspase-3 and poly (ADP-ribose) polymerase (PARP) were induced by atromentin in a dose-dependent manner. Furthermore, DNA fragmentation was also induced by this compound in a dose-dependent manner. These results show that atromentin potently induces apoptosis in U937 cells and that atromentin-induced apoptosis is related to the selective activation of caspases.



  1. Bhalla, K., A. M. Ibrado, E. Tourkina, C. Tang, S. Grant, G. Bullock, Y. Huang, V. Ponnathpur, and M. E. Mahoney. 1993. High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells. Blood 82: 3133- 3140
  2. Bradham, C. A., T. Qian, K. Streetz, C. Trautwein, D. A. Brenner, and J. J. Lemasters. 1998. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol. Cell. Biol. 18: 6353- 6364
  3. Choi, S. K., B. R. Seo, K. W. Lee, W. Cho, S. H. Jeong, and K. T. Lee. 2007. Saucernetin-7 isolated from Saururus chinensis induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol. Pharm. Bull. 30: 1516-1522
  4. Dantzer, F., V. Schreiber, C. Niedergang, C. Trucco, E. Flatter, G. De La Rubia, et al. 1999. Involvement of poly(ADP ribose) polymerase in base excission repair. Biochimie 81: 69-75
  5. De Almeida, C. J. and R. Linden. 2005. Phagocytosis of apoptotic cells: A matter of balance. Cell Mol. Life Sci. 62: 1532-1546
  6. Deveraux, Q. L. and J. C. Reed. 1999. IAP family proteins - suppressors of apoptosis. Genes Dev. 13: 239-252
  7. Evans, V. G. 1993. Multiple pathways to apoptosis. Cell Biol. Int. 17: 461-476
  8. Friesen, C., I. Herr, P. H. Krammer, and K. M. Debatin. 1996. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat. Med. 2: 574-577
  9. Gaylord, M. C. and L. R. Brady. 1971. Comparison of pigments in carpophores and saprophytic cultures of Paxillus panuoides and Paxillus atrotomentosus. J. Pharm. Sci. 60: 1503-1508
  10. Goodwin, C. J., S. J. Holt, S. Downes, and N. J. Marshall. 1995. Microculture tetrazolium assays: A comparison between two new tetrazolium salts, XTT and MTS. J. Immunol. Methods 179: 95-103
  11. Guo, Y. and N. Kyprianou. 1999. Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1- mediated apoptosis. Cancer Res. 59: 1366-1371
  12. Hanahan, D. and J. Folkman. 1996. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-364
  13. Hong, W. K. and M. B. Sporn. 1997. Recent advances in chemoprevention of cancer. Science 278: 1073-1077
  14. Hu, L., J. M. Gao, and J. K. Liu. 2001. Unusual poly (phenylacetyloxy) substituted 1,1':4',1"-terphenyl derivatives from fruiting bodies of the basidiomycete Thelephora ganbajum. Helv. Chem. Acta 84: 3342-3349<3342::AID-HLCA3342>3.0.CO;2-K
  15. Huang, P. and A. Oliff. 2001. Signaling pathways in apoptosis as potential targets for cancer therapy. Trends Cell Biol. 11: 343-348
  16. Janicke, R. U., M. L. Sprengart, M. R. Wati, and A. G. Porter. 1998. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 273: 9357-9360
  17. Kaufmann, S. H. 1980. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: A cautionary note. Cancer Res. 49: 5870-5878
  18. Lakka, S. S., C. S. Gondi, N. Yanamandra, W. C. Olivero, D. H. Dinh, M. Gujrati, and J. S. Rao. 2004. Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. Oncogene 23: 4681-4689
  19. Liu, J. K. 2006. Natural terphenyls: Developments in vascular angiogenesis. Free Radic. Biol. Med. 33: 1047-1060
  20. Maulik, N. and D. K. Das. 2002. Redox signaling in vascular angiogenesis. Free Radic. Biol. Med. 33: 1047-1060
  21. Nicholson, D. W., A. Ali, N. A. Thornberry, J. P. Vaillancourt, C. K. Gallant, Y. Gareau, P. R. Griffin, M. Labelle, and Y. A. Lazebnik. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37-43
  22. Pipper, A. A., A. Verma, J. Zhang, and S. H. Snyder. 1999. Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol. Sci. 20: 171-181
  23. Rosse, T., R. Olivier, L. Monney, M. Rager, S. Conus, I. Fellay, B. Jansen, and C. Borner. 1998. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391: 496-499
  24. Thorner, W. 1878. Ueber eigen in einer Agaricus-art vorkommenden chinonartigen K$\"{o}$rper. Chem. Ber. 11: 533-535
  25. Ujibe, M., S. Kanno, Y. Osanai, K. Koiwai, T. Ohtake, K. Kimura, K. Uwai, M. Takeshita, and M. Ishikawa. 2005. Octylcaggeate induced apoptosis in human leukemia U937 cells. Biol. Pharm. Bull. 28: 2338-2341
  26. Webster, K. A. 2003. Therapeutic angiogenesis: A complex problem requiring a sophisticated approach. Cardiovasc. Toxicol. 3: 283-298
  27. Woo, M., R. Hakem, M. S. Soengas, G. S. Duncan, A. Shahinian, D. Kagi, et al. 1998. Essential contribution of caspase-3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12: 806-819
  28. Zheng, C. J., M. J. Sohn, and W. G. Kim. 2006. Atromentin and leucomelone, the first inhibitors specific to enoyl-ACP reductase (FabK) of Streptococcus pneumoniae. J. Antibiot. 59: 808-812