title: Optimization of adiponectin-derived peptides for inhibition of cancer cell growth and signaling.
abstract: Adiponectin, an adipose tissue-excreted adipokine plays protective roles in metabolic and cardiovascular diseases and exerts anti-cancer activities, partially by interfering with leptin-induced signaling. Previously we identified the active site in the adiponectin protein, and generated both a nanomolar monomeric agonist of the adiponectin receptor (10-mer ADP355) and an antagonist (8-mer ADP400) to modulate various adiponectin receptor-mediated cellular functions. As physiologically circulating adiponectin forms multimeric complexes, we also generated an agonist dimer with improved biodistribution and in vitro efficacy. In the current report, we attempted to optimize the monomeric agonist structure. Neither extension of the peptide up to 14-mer analogs nor reinstallation of native residues in permissible positions enhanced significantly the activity profile. The only substitutions that resulted in 5-10-fold improved agonistic activity were the replacement of turn-forming Gly4 and Tyr7 residues with Pro and Hyp, respectively, yielding the more active native β-sheet structure. All peptides retained good stability in human serum exhibiting half-lives >2 h. The cellular efficacy and stability rankings among the peptides followed expected structure-activity relationship trends. To investigate whether simultaneous activation of adiponectin pathways and inhibition of leptin-induced signals can result in cytostatic and anti-oncogenic signal transduction processes, we developed a chimera of the leptin receptor antagonist peptide Allo-aca (placed to the N-terminus) and ADP355 (at the C-terminus). The in vitro anti-tumor activity and intracellular signaling of the chimera were dominated by the more active Allo-aca component. The ADP355 part, however, reversed unfavorable in vivo metabolic effects of the leptin receptor antagonist.
authors: Department of Biology, Temple University, Philadelphia, PA, 19122.
authors: Laszlo
authors: L
authors: Otvos
authors: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary.
authors: Ilona
authors: I
authors: Kovalszky
authors: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary.
authors: Julia
authors: J
authors: Olah
authors: Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, 19122.
authors: Roberta
authors: R
authors: Coroniti
authors: Institute of Bioanalytical Chemistry, Leipzig University, Leipzig, 04103, Germany.
authors: Daniel
authors: D
authors: Knappe
authors: Institute of Bioanalytical Chemistry, Leipzig University, Leipzig, 04103, Germany.
authors: Friederike I
authors: FI
authors: Nollmann
authors: Institute of Bioanalytical Chemistry, Leipzig University, Leipzig, 04103, Germany.
authors: Ralf
authors: R
authors: Hoffmann
authors: Florey Neurosciences Institutes, University of Melbourne, Victoria, 3010, Australia.|School of Chemistry, University of Melbourne, Victoria, 3010, Australia.
authors: John D
authors: JD
authors: Wade
authors: Department of Biomedical Sciences, Creighton University, Omaha, NE, 68178.
authors: Sandor
authors: S
authors: Lovas
authors: Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, 19122.
authors: Eva
authors: E
authors: Surmacz
mesh_terms: D052242:Adiponectin / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D052242:Adiponectin; D010455:Peptides
keywords: activity relationships; biodistribution; breast cancer; chimera; chronic myeloid leukemia; growth inhibition; ophthalmic cell models; proteolytic stability; structure