Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways
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
Pages 690-704 (15)
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.
Type I interferons, survival pathways, EGF receptor, MAPK, PI3K/AKT
Department of Biochemistry and Biophysics, II University of Naples, Via Costantinopoli 16, 80138, Naples, Italy.