γ-Glutamyl 16-diaminopropane derivative of vasoactive intestinal peptide: a potent anti-oxidative agent for human epidermoid cancer cells

• Published in: Amino acids 2010-08, Vol.39 (3), p.661-670
• Main Authors: Stiuso, Paola, Giuberti, Gaia, Lombardi, Angela, Dicitore, Alessandra, Limongelli, Vittorio, Cartenì, Maria, Abbruzzese, Alberto, Caraglia, Michele
• Format: Article
• Language: English
• Subjects: Akt; Analytical Chemistry; Antioxidants - pharmacology; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Extracellular signal-regulated kinases Erk-1/2; Humans; Life Sciences; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - metabolism; Neurobiology; Original Article; Oropharyngeal Neoplasms - drug therapy; Oropharyngeal Neoplasms - metabolism; oxidative stress; Oxidative Stress - drug effects; p38 kinase; Proliferation; Proteomics; Vasoactive intestinal peptide (VIP); Vasoactive Intestinal Peptide - analogs & derivatives; Vasoactive Intestinal Peptide - pharmacology; γ-Glutamyl 16 amine vasoactive intestinal peptide (VIP-DAP3)
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-010-0487-5

We previously demonstrated that the γ-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 γ-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.