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Y2 receptors decrease human pancreatic cancer growth and intracellular cyclic adenosine monophosphate levels
C D Liu1, L W Slice, A Balasubramaniam
1Department of Surgery, University of California-Los Angeles Center for the Health Sciences, USA.
Background:
Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo.
Methods:
The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro.
Results:
All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells.
Conclusions:
BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.
Insights
BIM-43004-1, a Y2 receptor agonist, significantly reduced pancreatic cancer growth in mice by decreasing cAMP levels. This synthetic peptide shows promise for treating pancreatic adenocarcinoma.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Peptide YY (PYY) is an enteric hormone that inhibits pancreatic function.
- Previous research indicated BIM-43004-1, a PYY analog, reduced mitochondrial activity in pancreatic cancer cells.
- The in vivo effects of PYY and BIM-43004-1 on pancreatic cancer growth were unexplored.
Purpose of the Study:
- To investigate the effects of PYY and BIM-43004-1 on pancreatic cancer growth in vivo.
- To assess the impact of these agents on tumor mass and receptor binding.
- To determine changes in intracellular cyclic adenosine monophosphate (cAMP) levels.
Main Methods:
- Human pancreatic cancer cells (Mia PaCa-2) were orthotopically transplanted into athymic mice.
- Mice received PYY or BIM-43004-1 (200 pmol/kg/hr) or saline via miniosmotic pumps for 2-4 weeks.
- Tumor mass, receptor binding, and intracellular cAMP levels were measured.
Main Results:
- BIM-43004-1 treatment decreased tumor mass by 60.5%, while PYY decreased it by 27.1%.
- Receptor binding studies quantified BIM-43004-1 binding affinity (Kd=4.5 nmol) and receptor density (27,000 receptors/cell).
- BIM-43004-1 reduced intracellular cAMP by 52.5%, compared to 15.3% for PYY.
Conclusions:
- BIM-43004-1, a Y2 agonist, binds to pancreatic cancer cells and suppresses tumor growth in vivo.
- The compound reduces intracellular cAMP levels, contributing to its anti-tumor effect.
- Adjuvant therapy with BIM-43004-1 may benefit pancreatic adenocarcinoma patients.