Gamma-glutamyl 16-diaminopropane derivative of vasoactive intestinal peptide: a potent anti-oxidative agent for human epidermoid cancer cells.

We previously demonstrated that the gamma-glutamyl 16 amine derivative of vasoactive intestinal peptide (VIP) acts as structural VIP agonist with affinity and potency higher than VIP. Herein, we have evaluated the effects of VIP and gamma-Gln16-diaminopropane derivative of VIP (VIP-DAP3) on the proliferation and protection from oxidative stress induced by hydrogen peroxide (H2O2) on epidermoid carcinoma cell lines. We have found that 10(-11) M VIP-DAP3 completely antagonized the inhibition induced by H2O2 on both cell proliferation and S-phase distribution while these effects were only partially antagonized by equimolar concentrations of VIP. Moreover, both oxidative stress and intracellular lipid oxidation induced by H2O2 were reduced by VIP and completely antagonized by VIP-DAP3. Thereafter, we have found that H2O2 increased p38 kinase activity and both HSP70 and HSP27 expression. VIP and VIP-DAP3 again antagonized these effects partially or totally, respectively. H2O2 reduced the activity of extracellular signal-regulated kinases Erk-1/2 and Akt, signalling proteins involved in proliferation/survival pathways. Again VIP restored the activity of both kinases while VIP-DAP3 caused indeed an increase of their activity as compared to untreated cells. These data suggest that VIP-DAP3 has a stronger anti-oxidative activity as compared to VIP likely based on its super-agonistic binding on the putative receptor.