Cancer Therapy

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The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways

  1. Michele Caraglia1,†,*,
  2. Monica Marra1,
  3. Caterina Viscomi2,3,
  4. Anna Maria D'Alessandro4,
  5. Alfredo Budillon1,
  6. Giuseppina Meo1,
  7. Claudio Arra5,
  8. Antonio Barbieri5,
  9. Ulf R Rapp6,
  10. Alfonso Baldi4,
  11. Pierfrancesco Tassone2,3,
  12. Salvatore Venuta2,3,
  13. Alberto Abbruzzese4,‡,*,
  14. Pierosandro Tagliaferri2,3

Article first published online: 26 JUL 2007

DOI: 10.1002/ijc.22964

Issue

International Journal of Cancer

International Journal of Cancer

Volume 121, Issue 10, pages 2317–2330, 15 November 2007

Additional Information

How to Cite

Caraglia, M., Marra, M., Viscomi, C., D'Alessandro, A. M., Budillon, A., Meo, G., Arra, C., Barbieri, A., Rapp, U. R., Baldi, A., Tassone, P., Venuta, S., Abbruzzese, A. and Tagliaferri, P. (2007), The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways. Int. J. Cancer, 121: 2317–2330. doi: 10.1002/ijc.22964

Author Information

  1. 1

    Experimental Pharmacology Unit, Experimental Oncology Department, National Cancer Institute Fondazione “G. Pascale”, Naples, Italy

  2. 2

    Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro. Italy

  3. 3

    Oncology Center “Germaneto”, Catanzaro, Italy

  4. 4

    Department of Biochemistry and Biophysics, II University of Naples, Naples, Italy

  5. 5

    Experimental Oncology Department, Animal Facility, National Cancer Institute Fondazione “G. Pascale”, Naples, Italy

  6. 6

    Institute of Medical Radiation and Cell Research (MSZ), University of Würzburg, 97078 Würzburg, Germany

  1. †

    Fax: +39-0815903813.

  2. ‡

    Fax: + 39-081-5665863.

*Experimental Pharmacology Unit, Experimental Oncology Department, National Cancer Institute Fondazione “G. Pascale”, Via Mariano Semmola, 80131 Naples, Italy

Publication History

  1. Issue published online: 25 SEP 2007
  2. Article first published online: 26 JUL 2007
  3. Manuscript Accepted: 6 JUN 2007
  4. Manuscript Received: 22 SEP 2006

Funded by

  • MIUR Rome. Grant Number: PRIN 2005
  • Associazione Italiana Ricerca sul Cancro (AIRC)
  • Italian Ministry of Health. Grant Numbers: FSN 2004, FSN 2005
  • Centro Regionale di Competenza di “Diagnostica e Farmaceutica Molecolari” of Regione Campania

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Keywords:

  • farnesyl transferase inhibitor;
  • interferon α;
  • epidermoid cancer;
  • apoptosis;
  • Ras

Abstract

Interferon α (IFNα) induces an EGF-Ras→Raf-1→Erk dependent survival pathway counteracting apoptosis induced by the cytokine. In this paper we have evaluated the effects of the combination between farnesyl-transferase inhibitor (FTI) R115777 and IFNα on the growth inhibition and apoptosis of cancer cells. Simultaneous exposure to R115777 and IFNα produced synergistic both antiproliferative and proapoptotic effects. In these experimental conditions, IFNα and R115777 completely antagonized the increased activity of both Ras and Erk-1/2 induced by IFNα and strongly reduced Akt activity. Furthermore, treatment with R115777 in combination with IFNα regimen induced tumor growth delay on established KB cell xenografts in nude mice, while the single agents were almost inactive. R115777 was again able to antagonize the Ras-dependent survival pathway induced by IFNα also in vivo. Raf-1, one of the downstream targets of Ras, has been reported to activate bcl-2 through displacement and/or phosphorylation of Bad. We have found that IFNα induced mitochondrial localization of Raf-1 that was antagonized by R115777. Moreover, IFNα increased Raf-1/bcl-2 immuno-conjugate formation and intracellular co-localization and enhanced phosphorylation of Bad at Ser 112 and again R115777 counteracted all these effects. Moreover, the use of plasmids encoding for dominant negative or dominant positive Raf-1 antagonized and potentiated, respectively, the co-immunoprecipitation between Raf-1 and bcl-2. In conclusion, FTI R115777 strongly potentiates the antitumor activity of IFNα both in vitro and in vivo through the inhibition of different survival pathways that are dependent from isoprenylation of intracellular proteins such as ras. © 2007 Wiley-Liss, Inc.

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