Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation

Laszlo Otvos, I. Kovalszky, Laura Scolaro, Andras Sztodola, Julia Olah, Marco Cassone, Daniel Knappe, Ralf Hoffmann, Sandor Lovas, Marcus P D Hatfield, G. Bekő, Suode Zhang, John D. Wade, Eva Surmacz

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Because of the presence of multiple leptin/receptor (ObR) interaction sites and diverse leptin activities, the literature lacks truly monofunctional leptin protein derivatives or fragments. To date, selective ObR antagonists have not been reported. We developed short, pharmacologically advantageous peptide analogs of ObRbinding site III of leptin that acted as selective ObR inhibitors without any partial agonistic activity. These reduced leptin-dependent growth and signaling in cancer cell lines at picomolar and low nanomolar concentrations. In immunocompromised mice the peptides suppressed the growth of rapidly proliferating orthotopic human breast cancer xenografts by 50% when administered either intraperitoneally (i.p.) or subcutaneously (s.c.) for 38 days at a 0.1 mg/kg/day dose. The peptides were distributed to the brain, and when added to growing C57BL/6 normal mice i.p., s.c., or orally, the lead antagonist accelerated normal weight increase without producing any toxic effects. Weight gain increases could not be observed after 10-12 days of treatment indicating that the mice became resistant to the central nervous system activity of leptin antagonists. However, in normal growing rats the intranasal administration at 0.1 mg/kg/day for 20 days resulted in a 2% net total body weight gain without signs of resistance induction. In addition to the potential of these peptides in drug development against primary and metastatic tumors and cachexia, our data confirm that resistance to leptin resides at the blood-brain barrier.

Original languageEnglish
Pages (from-to)117-125
Number of pages9
JournalBiopolymers - Peptide Science Section
Volume96
Issue number2
DOIs
Publication statusPublished - 2011

Fingerprint

Appetite Regulation
Leptin Receptors
Oncology
Leptin
Peptides
Neurology
Neoplasms
Hormones
Therapeutics
Weight Gain
Central Nervous System
Rats
Tumors
Brain
Lead
Cells
Intranasal Administration
Cachexia
Tissue
Derivatives

Keywords

  • Blood-brain barrier penetration
  • Breast cancer
  • Leptin-dependent tumors
  • Orthotopic mouse model
  • Peptidomimetic

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry

Cite this

Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation. / Otvos, Laszlo; Kovalszky, I.; Scolaro, Laura; Sztodola, Andras; Olah, Julia; Cassone, Marco; Knappe, Daniel; Hoffmann, Ralf; Lovas, Sandor; Hatfield, Marcus P D; Bekő, G.; Zhang, Suode; Wade, John D.; Surmacz, Eva.

In: Biopolymers - Peptide Science Section, Vol. 96, No. 2, 2011, p. 117-125.

Research output: Contribution to journalArticle

Otvos, L, Kovalszky, I, Scolaro, L, Sztodola, A, Olah, J, Cassone, M, Knappe, D, Hoffmann, R, Lovas, S, Hatfield, MPD, Bekő, G, Zhang, S, Wade, JD & Surmacz, E 2011, 'Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation', Biopolymers - Peptide Science Section, vol. 96, no. 2, pp. 117-125. https://doi.org/10.1002/bip.21377
Otvos, Laszlo ; Kovalszky, I. ; Scolaro, Laura ; Sztodola, Andras ; Olah, Julia ; Cassone, Marco ; Knappe, Daniel ; Hoffmann, Ralf ; Lovas, Sandor ; Hatfield, Marcus P D ; Bekő, G. ; Zhang, Suode ; Wade, John D. ; Surmacz, Eva. / Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation. In: Biopolymers - Peptide Science Section. 2011 ; Vol. 96, No. 2. pp. 117-125.
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