Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity

Peptides. 2013 Jun;44:127-34. doi: 10.1016/j.peptides.2013.03.027. Epub 2013 Apr 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Female
  • HT29 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Inbred C57BL
  • Molecular Mimicry
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Receptors, Leptin / antagonists & inhibitors*
  • Signal Transduction
  • Spheroids, Cellular / drug effects
  • Tissue Distribution
  • Weight Gain / drug effects

Substances

  • Antineoplastic Agents
  • D-Ser Allo-aca peptide
  • Intracellular Signaling Peptides and Proteins
  • Peptides
  • Receptors, Leptin