Skip to main content

Thank you for visiting nature.com. 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.

  • Original Paper
  • Published:

PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis

Abstract

Mutant p53-carrying tumors are often more resistant to chemotherapeutical drugs. We demonstrate here that the mutant p53-reactivating compound PRIMA-1MET acts synergistically with several chemotherapeutic drugs to inhibit tumor cell growth. Combined treatment with cisplatin and PRIMA-1MET resulted in a synergistic induction of tumor cell apoptosis and inhibition of human tumor xenograft growth in vivo in SCID mice. The induction of mutant p53 levels by chemotherapeutic drugs is likely to increase the sensitivity of tumor cells to PRIMA-1MET. Thus, the combination of PRIMA-1MET with currently used chemotherapeutic drugs may represent a novel and more efficient therapeutic strategy for treatment of mutant p53-carrying tumors.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bergh J, Norberg T, Sjogren S, Lindgren A and Holmberg L . (1995). Nat. Med., 1, 1029–1034.

  • Borresen-Dale AL . (2003). Hum. Mutat., 21, 292–300.

  • Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW and Vogelstein B . (1999). J. Clin. Invest., 104, 263–269.

  • Bykov VJ, Issaeva N, Selivanova G and Wiman KG . (2002a). Carcinogenesis, 23, 2011–2018.

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG and Selivanova G . (2002b). Nat. Med., 8, 282–288.

  • Cadwell C and Zambetti GP . (2001). Gene, 277, 15–30.

  • Campling BG and el-Deiry WS . (2003). Methods Mol. Med., 75, 53–77.

  • Foster BA, Coffey HA, Morin MJ and Rastinejad F . (1999). Science, 286, 2507–2510.

  • Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC and Kaelin Jr WG . (2003). Cancer Cell, 3, 403–410.

  • Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR and Selivanova G . (2003). Proc. Natl. Acad. Sci. USA, 100, 13303–13307.

  • Keshelava N, Zuo JJ, Chen P, Waidyaratne SN, Luna MC, Gomer CJ, Triche TJ and Reynolds CP . (2001). Cancer Res., 61, 6185–6193.

  • Matas D, Sigal A, Stambolsky P, Milyavsky M, Weisz L, Schwartz D, Goldfinger N and Rotter V . (2001). EMBO J., 20, 4163–4172.

  • Michael D and Oren M . (2003). Semin. Cancer Biol., 13, 49–58.

  • North S, Pluquet O, Maurici D, El-Ghissassi F and Hainaut P . (2002). Mol. Carcinogen., 33, 181–188.

  • O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace Jr AJ and Kohn KW . (1997). Cancer Res., 57, 4285–4300.

  • Ohnishi K, Ota I, Yane K, Takahashi A, Yuki K, Emoto M, Hosoi H and Ohnishi T . (2002). Mol. Cancer, 1, 4.

  • Ohnishi T, Matsumoto H, Wang X, Takahashi A, Tamamoto T and Ohnishi K . (1999). Int. J. Radiat. Biol., 75, 1095–1098.

  • Schmitt CA . (2003). Nat. Rev. Cancer, 3, 286–295.

  • Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, Grafstrom RC and Wiman KG . (1997). Nat. Med., 3, 632–638.

  • Sugikawa E, Hosoi T, Yazaki N, Gamanuma M, Nakanishi N and Ohashi M . (1999). Anticancer Res., 19, 3099–3108.

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

  • Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.

  • Wang W, Takimoto R, Rastinejad F and El-Deiry WS . (2003). Mol. Cell. Biol., 23, 2171–2181.

  • Weinstein JN, Myers TG, O’Connor PM, Friend SH, Fornace Jr AJ, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, van Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE and Paull KD . (1997). Science, 275, 343–349.

Download references

Acknowledgements

This work was supported by the Swedish Cancer Society (Cancerfonden), Cancerföreningen, Karolinska Institute, the Ingabritt & Arne Lundberg Foundation and EC FP5 and FP6 Funding. The information in this document is provided as is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at its sole risk and liability. The Community is not liable for any use that may be made of the information contained herein. We thank Bert Vogelstein, Johns Hopkins Oncology Center, for HCT116 cells, Peter Chumakov, Engelhard Institute of Molecular Biology, Moscow, for H1299-His175 cells and Farzan Rastinejad, Pfizer Central Research, for CP31398.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Klas G Wiman.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bykov, V., Zache, N., Stridh, H. et al. PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 24, 3484–3491 (2005). https://doi.org/10.1038/sj.onc.1208419

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208419

Keywords

This article is cited by

Search

Quick links