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 language | English |
|---|---|
| Pages (from-to) | 117-125 |
| Number of pages | 9 |
| Journal | Biopolymers |
| Volume | 96 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2011 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Biophysics
- Biomaterials
- Organic Chemistry
Cite this
Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation. / Otvos, Laszlo; Kovalszky, Ilona; Scolaro, Laura; Sztodola, Andras; Olah, Julia; Cassone, Marco; Knappe, Daniel; Hoffmann, Ralf; Lovas, Sándor; Hatfield, Marcus P D; Beko, Gabriella; Zhang, Suode; Wade, John D.; Surmacz, Eva.
In: Biopolymers, Vol. 96, No. 2, 2011, p. 117-125.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation
AU - Otvos, Laszlo
AU - Kovalszky, Ilona
AU - Scolaro, Laura
AU - Sztodola, Andras
AU - Olah, Julia
AU - Cassone, Marco
AU - Knappe, Daniel
AU - Hoffmann, Ralf
AU - Lovas, Sándor
AU - Hatfield, Marcus P D
AU - Beko, Gabriella
AU - Zhang, Suode
AU - Wade, John D.
AU - Surmacz, Eva
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78649369121&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649369121&partnerID=8YFLogxK
U2 - 10.1002/bip.21377
DO - 10.1002/bip.21377
M3 - Article
C2 - 20564005
AN - SCOPUS:78649369121
VL - 96
SP - 117
EP - 125
JO - Biopolymers
JF - Biopolymers
SN - 0006-3525
IS - 2
ER -