Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways

Curr Cancer Drug Targets. 2009 Aug;9(5):690-704. doi: 10.2174/156800909789056980. Epub 2009 Aug 1.


Interferon-a (IFN-a) is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-a is limited by the activation of tumour resistance mechanisms. In this regard, we have shown that IFN-a, at growth inhibitory concentrations, enhances the EGF-dependent Ras-->Erk signalling and decreases the adenylate cyclase/cAMP pathway activity in cancer cells; both effects represent escape mechanisms to the growth inhibition and apoptosis induced by IFN-a. The selective targeting of these survival pathways might enhance the antitumor activity of IFN-ain cancer cells, as shown by: i) the combination of selective EGF receptor tyrosine kinase inhibitor (gefitinib) and IFN-a having cooperative anti-tumour effects; ii) the farnesyl-transferase inhibitor R115777 strongly potentiating the anti-tumour activity of IFN-a both in vitro and in vivo through the inhibition of different escape mechanisms that are dependent on isoprenylation of intracellular proteins such as ras; iii) the cAMP reconstituting agent (8-Br-cAMP) enhancing the pro-apoptotic activity of IFN-alpha. IFN-beta is a multifunctional cytokine binding the same receptor of IFN-alpha, but with higher affinity (10-fold) and differential structural interactions. We recently showed that IFN-beta is considerably more potent than IFN-alpha in its anti-tumour effect through the induction of apoptosis and/or cell cycle arrest in S-phase. The emergence of long-acting pegylated forms of IFN-beta makes this agent a promising anti-cancer drug. These observations open a new scenario of anticancer intervention able to strengthen the antitumor activity of IFN-alpha or to use more potent type I IFNs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Survival / drug effects*
  • Forecasting
  • Gene Expression Regulation / drug effects
  • Humans
  • Interferon Type I / metabolism*
  • Interferon Type I / pharmacology*
  • Interferon Type I / therapeutic use
  • Models, Biological
  • Neoplasms / drug therapy
  • Protein Processing, Post-Translational / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Antineoplastic Agents
  • Interferon Type I