Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways

Title: Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways

Volume: 9 Issue: 5

Author(s): M. Caraglia, M. Marra, P. Tagliaferri, S. W.J. Lamberts, S. Zappavigna, G. Misso, F. Cavagnini, G. Facchini, A. Abbruzzese, L. J. Hofland and G. Vitale

Affiliation:

Keywords: Type I interferons, survival pathways, EGF receptor, MAPK, PI3K/AKT

Abstract: Interferon-α (IFN-α) is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-α is limited by the activation of tumour resistance mechanisms. In this regard, we have shown that IFN-α, 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-α. The selective targeting of these survival pathways might enhance the antitumor activity of IFN-α in cancer cells, as shown by: i) the combination of selective EGF receptor tyrosine kinase inhibitor (gefitinib) and IFN-α having cooperative anti-tumour effects; ii) the farnesyl-transferase inhibitor R115777 strongly potentiating the anti-tumour activity of IFN-α 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-BrcAMP) enhancing the pro-apoptotic activity of IFN-α. IFN-β is a multifunctional cytokine binding the same receptor of IFN-α, but with higher affinity (10-fold) and differential structural interactions. We recently showed that IFN- β is considerably more potent than IFN-α 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-β 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-α or to use more potent type I IFNs.

Cite this article as:

Caraglia M., Marra M., Tagliaferri P., Lamberts W.J. S., Zappavigna S., Misso G., Cavagnini F., Facchini G., Abbruzzese A., Hofland J. L. and Vitale G., Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways, Current Cancer Drug Targets 2009; 9 (5) . https://dx.doi.org/10.2174/156800909789056980