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The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway

Oncogene volume 19, pages 1206–1214 (2000)Cite this article

Abstract

The phosphoaminothiol WR1065, the active metabolite of the pro-drug amifostine (WR2721), protects cultured cells and tissues against cytotoxic exposure to radiation or chemotherapeutic agents. We show here that WR1065 and the pro-drug WR2721 activate the p53 tumor suppressor protein and induce the expression of the cyclin-dependent kinase inhibitor p21waf-1 in the breast cancer cell line MCF-7, and in the mouse fibroblast cell line balb/c 3T3. Using two MCF-7 derived cell lines, MN1 and MDD2, we show that induction of p21waf-1 is detectable in MN1 (expressing a functional p53) but not in MDD2 (p53 disabled). These effects are observed at concentrations of WR1065 (0.5 to 1 mM) identical to those required to protect against cytotoxicity by hydrogen peroxide. Induction of p53 is not prevented by addition of aminoguanidine, an inhibitor of Cu-dependent amine-oxidases which blocks the extra-cellular degradation of WR1065 into toxic metabolites. Moreover, spermidine, a natural polyamine structurally related to amifostine, does not activate p53. Induction of p53 by WR1065 results in a delay in the G1/S transition in MCF-7 and MN-1 cells, but not in the p53 disabled cells MDD2. These data indicate that WR1065, a polyamine analog with thiol anti-oxidant properties, activates a cell cycle check-point involving p53.

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References

  • An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV and Neckers LM. . 1998 Nature 392: 405–408.

  • Bacus SS, Yarden Y, Oren M, Chin DM, Lyass L, Zelnick CR, Kazarov A, Toyofuku W, Gray-Bablin J, Beerli RR, Hynes NE, Nikiforov M, Haffner R, Gudkov A and Keyomarsi K. . 1996 Oncogene 12: 2535–2547.

  • Bissonnette N and Hunting DJ. . 1998 Oncogene 16: 3461–3469.

  • Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD and Fahey RC. . 1988 Cancer Res. 48: 3634–3640.

  • Capizzi RL. . 1996 Eur. J Cancer 32A: Suppl 4 S5–S16.

  • Cho Y, Gorina S, Jeffrey PD and Pavletich NP. . 1994 Science 265: 346–355.

  • Clark LS, Albertini RJ and Nicklas JA. . 1996 Carcinogenesis 17: 2647–2653.

  • Delmolino L, Band H and Band V. . 1993 Carcinogenesis 14: 827–832.

  • Donato NJ and Perez M. . 1998 J. Biol. Chem. 273: 5067–5072.

  • Graeber TG, Peterson JF, Tsia M, Monica K, Fornace AJJ and Giaccia AJ. . 1994 Mol. Cell. Biol. 14: 6264–6277.

  • Grdina DJ, Constantinou A, Shigematsu N and Murley JS. . 1994 Radiat. Res. 138: 44–52.

  • Grdina DJ, Nagy B, Hill CK, Wells RL and Peraino C. . 1985 Carcinogenesis 6: 929–931.

  • Grdina DJ, Shigematsu N, Dale P, Newton GL, Aguilera JA and Fahey RC. . 1995 Carcinogenesis 16: 767–774.

  • Grdina DJ and Sigdestad CP. . 1992 Cell Prolif. 25: 23–29.

  • Greenblatt MS, Bennett WP, Hollstein M and Harris CC. . 1994 Cancer Res. 54: 4855–4878.

  • Hainaut P and Hollstein M. . 2000 Adv. Cancer Res. 77: 81–137.

  • Hainaut P and Milner J. . 1993 Cancer Res. 53: 4469–4473.

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW. . 1991 Cancer Res. 51: 6304–6311.

  • Korst AE, Boven E, van der Sterre ML, Fichtinger-Schepman AM and van der Vijgh WJ. . 1997 Br. J. Cancer 75: 1439–1446.

  • Korst AE, Boven E, van der Sterre ML, Fichtinger-Schepman AM and van der Vijgh WJ. . 1998 Eur. J. Cancer 34: 412–416.

  • Kramer DL, Vujcic S, Diegelman P, Alderfer J, Miller JT, Black JD, Bergeron RJ and Porter CW. . 1999 Cancer Res. 59: 1278–1286.

  • Leroy D, Heriche JK, Filhol O, Chambaz EM and Cochet C. . 1997 J. Biol. Chem. 272: 20820–20827.

  • Linke SP, Clarkin KC, Di Leonardo A, Tsou A and Wahl GM. . 1996 Genes Dev. 10: 934–947.

  • List AF, Heaton R, Glinsmann-Gibson B and Capizzi RL. . 1998 Leukemia 12: 1596–1602.

  • Liu SC, Murley JS, Woloschak G and Grdina DJ. . 1997 Carcinogenesis 18: 2457–2459.

  • Loignon M, Fetni R, Gordon AJ and Drobetsky EA. . 1997 Cancer Res. 57: 3390–3394.

  • Martinez JD, Pennington ME, Craven MT, Warters RL and Cress AE. . 1997 Cell Growth Differ. 8: 941–949.

  • Meek DW. . 1998 Cell Signal 10: 159–166.

  • Meier T and Issels RD. . 1995 Biochem. Pharmacol. 50: 489–496.

  • Milligan JR, Aguilera JA, Wu CC, Paglinawan RA, Nguyen TT, Wu D and Ward JF. . 1997 Radiat. Res. 148: 325–329.

  • Mitchell JA, Rupert J, Leyser A and Judd GG. . 1998 Biochem. J. 335: 329–334.

  • Murley JS, Constantinou A, Kamath NS and Grdina DJ. . 1997 Cell Prolif. 30: 283–294.

  • Piette J, Piret B, Bonizzi G, Schoonbroodt S, Merville MP, Legrand-Poels S and Bours V. . 1997 Biol. Chem. 378: 1237–1245.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B. . 1997 Nature 389: 300–305.

  • Rainwater R, Parks D, Anderson ME, Tegtmeyer P and Mann K. . 1995 Mol. Cell. Biol. 15: 3892–3903.

  • Schiller JH, Storer B, Berlin J, Wittenkeller J, Larson M, Pharo L and Berry W. . 1996 J. Clin. Oncol. 14: 1913–1921.

  • Shaulian E, Zauberman A, Ginsberg D and Oren M. . 1992 Mol. Cell. Biol. 12: 5581–5592.

  • Smoluk GD, Fahey RC, Calabro-Jones PM, Aguilera JA and Ward J. . 1988 Cancer Res. 48: 3641–3647.

  • Treskes M, Boven E, Holwerda U, Pinedo HM and van der Vijgh WJ. . 1992 Cancer Res. 52: 2257–2260.

  • Treskes M, Boven E, van de Loosdrecht AA, Wijffels JF, Cloos J, Peters GJ, Pinedo HM and van der Vijgh WJ. . 1994 Eur. J. Cancer 30A: 183–187.

  • Vaughan AT, Grdina DJ, Meechan PJ, Milner AE and Gordon DJ. . 1989 Br. J. Cancer 60: 893–896.

  • Verhaegh GW, Parat MO, Richard MJ and Hainaut P. . 1998 Mol. Carcinog. 21: 205–214.

  • Verhaegh GW, Richard MJ and Hainaut P. . 1997 Mol. Cell. Biol. 17: 5699–5706.

  • Woloschak GE, Pauneski T, Chang-Liu CM and Grdina DJ. . 1995 Cancer Res. 55: 4788–4792.

  • Wyatt I, Moore RB and Smith LL. . 1989 Int. J. Radiat. Biol. 55: 463–472.

  • Yuhas JM. . 1980 Cancer Res. 40: 1519–1524.

  • Zhang X, Lai PP and Taylor YC. . 1992 Int. J. Radiat. Oncol Biol Phys. 42: 713–719.

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Acknowledgements

The authors thank Drs Ruggero Montesano and Janet Hall for critical reading of the manuscript and Dr M Oren for the kind gift of MN1 and MDD2 cells. This work is supported by a pre-clinical research grant from USB Pharma, and a research grant from l'Association de Recherche sur le Cancer. G Verhaegh, F El-Ghissassi and S North were recipients of a Special Training Award of the International Agency for Research on Cancer. S North is recipient of a post-doctoral fellowship from La Ligue Nationale de Recherche sur le Cancer.

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  1. S North and F El-Ghissassi: S North and F El-Ghissassi contributed equally to this paper

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  1. Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon, 69372, France

    S North, F El-Ghissassi, O Pluquet, G Verhaegh & P Hainaut

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North, S., El-Ghissassi, F., Pluquet, O. et al. The cytoprotective aminothiol WR1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway. Oncogene 19, 1206–1214 (2000). https://doi.org/10.1038/sj.onc.1203413

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