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

Michele Caraglia, Monica Marra, Caterina Viscomi, Anna Maria D'Alessandro, Alfredo Budillon, Giuseppina Meo, Claudio Arra, Antonio Barbieri, Ulf R. Rapp, Alfonso Baldi, Pierfrancesco Tassone, Salvatore Venuta, Alberto Abbruzzese, Pierosandro Tagliaferri

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2317-2330
Number of pages14
JournalInternational Journal of Cancer
Volume121
Issue number10
DOIs
Publication statusPublished - Nov 15 2007

Fingerprint

tipifarnib
Farnesyltranstransferase
Interferons
Transferases
Protein Prenylation
Phosphorylation
Apoptosis
KB Cells
Growth
Immunoprecipitation
Epidermal Growth Factor
Heterografts
Nude Mice

Keywords

  • Apoptosis
  • Epidermoid cancer
  • Farnesyl transferase inhibitor
  • Interferon α
  • Ras

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways. / Caraglia, Michele; Marra, Monica; Viscomi, Caterina; D'Alessandro, Anna Maria; Budillon, Alfredo; Meo, Giuseppina; Arra, Claudio; Barbieri, Antonio; Rapp, Ulf R.; Baldi, Alfonso; Tassone, Pierfrancesco; Venuta, Salvatore; Abbruzzese, Alberto; Tagliaferri, Pierosandro.

In: International Journal of Cancer, Vol. 121, No. 10, 15.11.2007, p. 2317-2330.

Research output: Contribution to journalArticle

Caraglia, M, Marra, M, Viscomi, C, D'Alessandro, AM, Budillon, A, Meo, G, Arra, C, Barbieri, A, Rapp, UR, Baldi, A, Tassone, P, Venuta, S, Abbruzzese, A & Tagliaferri, P 2007, 'The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways', International Journal of Cancer, vol. 121, no. 10, pp. 2317-2330. https://doi.org/10.1002/ijc.22964
Caraglia, Michele ; Marra, Monica ; Viscomi, Caterina ; D'Alessandro, Anna Maria ; Budillon, Alfredo ; Meo, Giuseppina ; Arra, Claudio ; Barbieri, Antonio ; Rapp, Ulf R. ; Baldi, Alfonso ; Tassone, Pierfrancesco ; Venuta, Salvatore ; Abbruzzese, Alberto ; Tagliaferri, Pierosandro. / The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways. In: International Journal of Cancer. 2007 ; Vol. 121, No. 10. pp. 2317-2330.
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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.",
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AU - Viscomi, Caterina

AU - D'Alessandro, Anna Maria

AU - Budillon, Alfredo

AU - Meo, Giuseppina

AU - Arra, Claudio

AU - Barbieri, Antonio

AU - Rapp, Ulf R.

AU - Baldi, Alfonso

AU - Tassone, Pierfrancesco

AU - Venuta, Salvatore

AU - Abbruzzese, Alberto

AU - Tagliaferri, Pierosandro

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