title: Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity.
abstract: The obesity hormone leptin has been implicated in the development and progression of different cancer types, and preclinical studies suggest that targeting leptin signaling could be a new therapeutic option for the treatment of cancer, especially in obese patients. To inhibit pro-neoplastic leptin activity, we developed leptin receptor (ObR) peptide antagonists capable of blocking leptin effects in vitro and in vivo. Our lead compound (Allo-aca), however, crosses the blood-brain-barrier (BBB), inducing undesirable orexigenic effects and consequent weight gain. Thus, redesigning Allo-aca to uncouple its central and peripheral activities should produce a superior compound for cancer treatment. The aim of this study was to generate novel Allo-aca analogs and test their biodistribution in vivo and anti-neoplastic activity in vitro in breast and colorectal cancer cells. Examination of several Allo-aca analogs resulted in the identification of the peptidomimetic, d-Ser, that distributed only in the periphery of experimental animals. d-Ser inhibited leptin-dependent-proliferation of ObR-positive breast and colorectal cancer cells in vitro at 1nM concentration without exhibiting any partial agonistic activity. d-Ser efficacy was demonstrated in monolayer and three-dimensional cultures, and its antiproliferative action was associated with the inhibition of several leptin-induced pathways, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT, cyclin D1, and E-cadherin. In conclusion, d-Ser is the first leptin-based peptidomimetic featuring peripheral ObR antagonistic activity. The novel peptide may serve as a prototype to develop new therapeutics, particularly for the management of obesity-related cancers.
authors.affiliation: Temple University, Sbarro Institute for Cancer Reserach and Molecular Medicine, Philadelphia, PA 19122, USA. serena.beccari@gmail.com
authors.forename: Serena
authors.initials: S
authors.lastname: Beccari
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
authors.forename: Eva
authors.initials: E
authors.lastname: Surmacz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects; D014018:Tissue Distribution; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C585337:D-Ser Allo-aca peptide; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D054411:Receptors, Leptin