A cyclic chimeric interferon-alpha2b peptide induces apoptosis in tumor cells.
Interferons alpha (IFNsalpha) are a family of related proteins exhibiting antiviral, antiproliferative and immunoregulatory activities. Although IFNsalpha have been widely employed for the pharmacological treatment of different types of cancer, the therapeutic efficacy occasionally can be diminished by the appearance of side effects, neutralizing antibodies or tumor resistance. In the search of mimetic peptides of the IFN-alpha2b molecule, we have recently synthesized a chimeric cyclic peptide that inhibits IFN-alpha2b binding to its receptor and exerts an IFN-like antiproliferative activity. In order to study the mechanism of growth inhibition of the cyclic chimera, we evaluated its ability to induce cell cycle arrest or apoptosis in WISH cells. We found that the chimeric peptide did not cause a cell cycle arrest, although the entire IFN-alpha2b molecule did modify cell cycle by increasing the number of S-phase cells. In spite of this difference, both molecules were able to induce apoptosis through the activation of caspases 8 and 9, indicating the involvement of death receptor and mitochondrial pathways. In addition, both peptidic derivative and IFN-alpha2b altered the expression of Bcl-2 family proteins and induced the release of cytochrome C to cytosol, supporting the participation of mitochondrial pathway in the induction of apoptosis. In conclusion, we demonstrated that the chimeric cyclic peptide behaved as a potent inducer of apoptosis and it could be a potentially useful agent for the treatment of certain malignancies.
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Viviana C
VC
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Peña
Clara
C
Roquin
Leonor P
LP
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000502:physiology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D045304:Cytochromes c; D020169:Caspases