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.
|Titolo:||Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways|
|Parole Chiave:||EGF receptor; MAPK; PI3K/AKT; Survival pathways; Type I interferons|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||ago-2009|
|Digital Object Identifier (DOI):||10.2174/156800909789056980|
|Appare nelle tipologie:||01 - Articolo su periodico|