Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines


3-3′-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH:quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin (CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 μ M dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53 (RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADP-ribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


  • Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA et al. (2003). J Biol Chem 278: 10368–10373.

  • Asher G, Lotem J, Cohen B, Sachs L, Shaul Y . (2001). Proc Natl Acad Sci USA 98: 1188–1193.

  • Benhar M, Dalyot I, Engelberg D, Levitzki A . (2001). Mol Cell Biol 21: 6913–6926.

  • Brozovic A, Fritz G, Christmann M, Zisowsky J, Jaehde U, Osmak M et al. (2004). Int J Cancer 112: 974–985.

  • Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG . (1997). Nature 385: 123–125.

  • Danson S, Ward TH, Butler J, Ranson M . (2004). Cancer Treat Rev 30: 437–449.

  • El-Deiry WS . (2003). Oncogene 22: 7486–7495.

  • Goktas S, Crawford ED . (1999). Semin Oncol 26: 162–173.

  • Huang S, Shu L, Dilling MB, Easton J, Harwood FC, Ichijo H et al. (2003). Mol Cell 11: 1491–1501.

  • Lewis A, Ough M, Li L, Hinkhouse MM, Ritchie JM, Spitz DR et al. (2004). Clin Cancer Res 10: 4550–4558.

  • Madari H, Panda D, Wilson L, Jacobs RS . (2003). Cancer Res 63: 1214–1220.

  • Mansouri A, Ridgway LD, Korapati AL, Zhang Q, Tian L, Wang Y et al. (2003). J Biol Chem 278: 19245–19256.

  • Martinez LA, Yang J, Vazquez ES, Rodriguez-Vargas Mdel C, Olive M, Hsieh JT et al. (2002). Carcinogenesis 23: 1289–1296.

  • Nishiyama H, Habuchi T, Watanabe J, Teramukai S, Tada H, Ono Y et al. (2004). Eur Urol 45: 176–181.

  • Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ et al. (2004). Mol Pharmacol 65: 1238–1247.

  • Southgate J, Hutton KA, Thomas DF, Trejdosiewicz LK . (1994). Lab Invest 71: 583–594.

  • Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y et al. (2004). EMBO J 23: 1889–1899.

  • Vasilevskaya IA, Rakitina TV, O'Dwyer PJ . (2004). Mol Pharmacol 65: 235–243.

  • Vogelstein B, Lane D, Levine AJ . (2000). Nature 408: 307–310.

  • Watanabe J, Nishiyama H, Okubo K, Takahashi T, Toda Y, Habuchi T et al. (2004). Urology 63: 989–993.

  • Weller M . (1998). Cell Tissue Res 292: 435–445.

  • Wu GS . (2004). Cancer Biol Ther 3: 156–161.

  • Yamamoto K, Ichijo H, Korsmeyer SJ . (1999). Mol Cell Biol 19: 8469–8478.

  • Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ . (2003). J Biol Chem 278: 23432–23440.

  • Zhang Y, Chen F . (2004). Cancer Res 64: 1902–1905.

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to O Ogawa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Watanabe, J., Nishiyama, H., Matsui, Y. et al. Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines. Oncogene 25, 2500–2508 (2006).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • urogenital cancer
  • cisplatin
  • dicoumarol
  • p53
  • JNK

This article is cited by


Quick links