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Diethyldithiocarbamate can induce two different type of death: Apoptosis and necrosis mediating the differential MAP kinase activation and redox regulation in HL60 cells

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Abstract

Although apoptosis and necrosis have been considered different pathways to cell death, only one compound induces both types of cell death. Diethyldithiocarbamate (DDC) has been shown to have antioxidant or prooxidant effects in several different systems. We observed in our present study that DDC induced not only apoptosis but also necrosis depending on its dosage in HL60 premyelocytic leukemia cells. Moreover, in hypoxia cell culture conditions, DDC-induced necrotic cells decreased but DDC-induced apoptosis continued. We investigated the DDC-induced different cell death mechanisms as they are correlated with reactive oxygen species (ROS). High-dose DDC-induced necrotic cell death is thought to depend on the increase of intracellular ROS, while low-dose DDC-induced apoptosis is thought to depend on changes of the intracellular redox state by the transporting of external metal ions. There was no sequential or quantitative change of Bcl-2 family proteins in DDC-induced apoptotic or necrotic pathways. However, the mitochondrial transmembrane potential was remarkably decreased in the DDC-induced necrosis. Finally, duration of c-Jun N-terminal kinase (JNK) activation resulted in different types of cell death. (Mol Cell Biochem 265: 123–132, 2004)

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References

  1. Wyllie AH, Kerr JFR, Currie AR: Cell death: The significance of apop-tosis. Int Rev Cytol 68: 251–306, 1980

    Google Scholar 

  2. Kitanaka C, Kuchino Y: Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ 6: 508–515, 1999

    Google Scholar 

  3. Fiers W, Beyaert R, Declercq W, Vandenabeele P: More than one way to die: Apoptosis, necrosis and reactive oxygen damage. Oncogene 18: 7719–7730, 1999

    Google Scholar 

  4. Robinson MJ, Cobb MH: Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9: 180–186, 1997

    Google Scholar 

  5. Adams JM, Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science 281: 1322–1326, 1998

    Google Scholar 

  6. Shi Y: Mechanisms of caspase activation and inhibition during apopto-sis. Mol Cell 9: 459–470, 2002

    Google Scholar 

  7. Sellers EM, Naranjo CA, Peachey JE: Drug therapy: Drugs to decrease alcohol consumption. N Engl J Med 305: 1255–1262, 1981

    Google Scholar 

  8. Sunderman FW: The extended therapeutic role of dithiocarb (sodium diethyldithiocarbamate) from nickel poisoning to AIDS. Ann Clin Lab Sci 22: 245–248, 1992

    Google Scholar 

  9. Reisinger EC, Kern P, Ernst M, Bock P, Flad HD, Dietrich M, German DTC Study Group: Inhibition of HIV progression by dithiocarb. Lancet 335: 679–682, 1990

    Google Scholar 

  10. Hadjiolov D, Frank N, Moog C, Spirov K: Proline dithiocarbamate inhibits N-nitrosodiethylamine induced liver carcinogenesis. J Cancer Res Clin Oncol 118: 401–404, 1992

    Google Scholar 

  11. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ: Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241–251, 1993

    Google Scholar 

  12. Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen DE: Bcl-2 inhibition of neural death: Decreased generation of reactive oxygen species. Science 262: 1274–1277, 1993

    Google Scholar 

  13. Abello PA, Fidler SA, Bulkley GB, Buchman TG: Antioxidants mod-ulate induction of programmed endothelial cell death (apoptosis) by endotoxin. Arch Surg 129: 134–140, 1994

    Google Scholar 

  14. Hong HJ, Loh SH, Yen MH: Suppression of the development of hyper-tension by the inhibitor of inducible nitric oxide synthase. Br J Pharma-col 131: 631–637, 2000

    Google Scholar 

  15. Li WG, Coppey L, Weiss RM, Oskarsson HJ: Antioxidant therapy attenuates JNK activation and apoptosis in the remote noninfarcted myocardium after large myocardial infarction. Biochem Biophys Res Commun 280: 353–357, 2001

    Google Scholar 

  16. Long SM, Laubach VE, Tribble CG, Kaza AK, Fiser SM, Cassada DC, Kern JA, Kron IL: Pyrrolidine dithiocarbamate reduces lung reperfusion injury. J Surg Res 112: 12–18, 2003

    Google Scholar 

  17. Brennan P, O'Neill LAJ: 2-Mercaptoethanol restores the ability of nu-clear factor kB(NF-kB) to bind DNAin nuclear extracts from interleukin 1-treated cells incubated with pyrollidine dithiocarbamate (PDTC). Ev-idence for oxidation of glutathione in the mechanism of inhibition of NF-kB by PDTC. Biochem J 320: 975–981, 1996

    Google Scholar 

  18. Guchelaar HJ, Vermes I, Koopmans RP, Reutelingsperger CPM, Haanen C: Apoptosis-and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: A quantitative pharmacodynamic model. Cancer Chemother Pharmacol 42: 77–83, 1998

    Google Scholar 

  19. Mammone T, Gan D, Collins D, Lockshin RA, Marenus K, Maes D: Successful separation of apoptosis and necrosis pathways in HaCaT keratinocyte cells induced by UVB irradiation. Cell Biol Toxicol 16: 293–302, 2000

    Google Scholar 

  20. Kimoto-Kinoshita S, Nishida S, Tomura TT: Age-related change of antioxidant capacities in the cerebral cortex and hippocampus of stroke-prone spontaneously hypertensive rats. Neurosci Lett 273: 41–44, 1999

    Google Scholar 

  21. Heikkila RE, Cabbat FS, Cohen G: In vivo inhibition of superoxide dismutase in mice by diethyldithiocarbamate. J Biol Chem 251: 2182–2185, 1976

    Google Scholar 

  22. Shimizu S, Eguchi Y, Kamiike W, Waguri S, Uchiyama Y, Matsuda H, Tsujimoto Y: Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13: 21–29, 1996

    Google Scholar 

  23. Marshall CJ: Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell 80: 179–185, 1995

    Google Scholar 

  24. Ragione FD, Cucciolla V, Borriello A, Pietra VD, Manna C, Galletti P, Zappia V: Pyrrolidine dithiocarbamate induces apoptosis by a cy-tochrome c-dependent mechanism. Biochem Biophys Res Commun 268: 942–946, 2000

    Google Scholar 

  25. Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW: Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94: 339–352, 1998

    Google Scholar 

  26. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X: Bid, a Bcl2 in-teracting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490, 1998

    Google Scholar 

  27. Matsumura H, Shimizu Y, Ohsawa Y, Kawahara A, Uchiyama Y, Nagata S: Necrotic death pathway in Fas receptor signaling. J Cell Biol 151: 1247–1256, 2000

    Google Scholar 

  28. Nobel CSI, Kimland M, Lind B, Orenius S, Slater AFG: Dithiocarba-mates induce apoptosis in thymocyytes by raising the intracellular level of redox-active copper. J Biol Chem 270: 26202–26208, 1995

    Google Scholar 

  29. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H: Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17: 2596–2606, 1998

    Google Scholar 

  30. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 sig-naling pathways. Science 275: 90–94, 1997

    Google Scholar 

  31. Ichijo H: From receptors to stress-activated MAP kinases. Oncogene 18: 6087–6093, 1999

    Google Scholar 

  32. Kanno S, Matsukawa E, Miura A, Shouji A, Asou K, Ishikawa M: Diethyldithiocarbamate-induced cytotoxicity and apoptosis in lukemia cell lines. Biol Pharm Bull 26: 964–968, 2003

    Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry & Oncology, Kinki University School of Medicine, Osaka-sayama, Osaka 589-8511, Japan

    Saori Kimoto-Kinoshita & Takanori T. Tomura

  2. Department of Pharmacotherapy, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-osaka, Osaka 577-5802, Japan

    Shozo Nishida

Authors
  1. Saori Kimoto-Kinoshita
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  2. Shozo Nishida
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  3. Takanori T. Tomura
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Kimoto-Kinoshita, S., Nishida, S. & Tomura, T.T. Diethyldithiocarbamate can induce two different type of death: Apoptosis and necrosis mediating the differential MAP kinase activation and redox regulation in HL60 cells. Mol Cell Biochem 265, 123–132 (2004). https://doi.org/10.1023/B:MCBI.0000044366.32073.2d

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  • DOI: https://doi.org/10.1023/B:MCBI.0000044366.32073.2d

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