Emerging strategies to strengthen the anti-tumour activity of type I interferons: overcoming survival pathways.
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.
Caraglia
M
M
Department of Biochemistry and Biophysics, II University of Naples, 80138, Naples, Italy. Michele.Caraglia@unina2.it
Marra
M
M
Tagliaferri
P
P
Lamberts
S W J
SW
Zappavigna
S
S
Misso
G
G
Cavagnini
F
F
Facchini
G
G
Abbruzzese
A
A
Hofland
L J
LJ
Vitale
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects*; D005544:Forecasting; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D007370:Interferon Type I