Z-360, a novel therapeutic agent for pancreatic cancer, prevents up-regulation of ephrin B1 gene expression and phosphorylation of NR2B via suppression of interleukin-1 β production in a cancer-induced pain model in mice.

Abstract

BACKGROUND:

Z-360 is an orally active cholecystokinin-2 (CCK2)/gastrin receptor antagonist currently under development as a therapeutic drug for pancreatic cancer. It was previously reported that Z-360 treatment in combination with gemcitabine prolonged the survival period in a lethal pancreatic cancer xenograft model in mice. In a phase Ib/IIa clinical study, Z-360 treatment displayed a trend of reduced pain in patients with advanced pancreatic cancer in combination with gemcitabine including analgesics such as opioids. Here, we investigated the mechanism of analgesic action of Z-360 in a severe cancer-induced pain model in mice, which is considered to be opioid-resistant, by examining ephrin B1 gene expression, N-methyl-D-aspartate receptor NR2B subunit phosphorylation, and interleukin-1β (IL-1β) production.

RESULTS:

In a mouse model of cancer-induced pain, ephrin B1 gene expression in dorsal root ganglia (DRGs) and the phosphorylation of NR2B in the spinal cord were induced. Z-360 treatment inhibited both ephrin B1 gene expression and the phosphorylation of NR2B. In addition, IL-1β production increased in the cancer-inoculated hind paw of mice, but could be suppressed by treatment with Z-360. Moreover, we observed that the CCK1 receptor antagonist devazepide similarly suppressed up-regulation of ephrin B1 gene expression and IL-1β production, and that the intraperitoneal injection of sulfated CCK-8 induced the production of IL-1β in the cancer-inoculated region.

CONCLUSIONS:

We have identified a novel pain cascade, in which IL-1β production in cancer-inoculated regions induces ephrin B1 gene expression in DRGs and then ephrin B1 enhances the tyrosine phosphorylation of NR2B via Eph B receptor in the spinal cord. Notably, Z-360 relieves cancer-induced pain by preventing this pain cascade through the suppression of IL-1β production, likely via the blockade of CCK1 receptor. The pre-clinical results presented here support the analgesic action of Z-360 in pancreatic cancer patients with severe, opioid-resistant pain. Pre-clinical and clinical results have demonstrated that Z-360 combined with gemcitabine represents a promising pancreatic cancer therapy approach with characteristic analgesic effects in addition to the prolongation of survival.

• Authors: Yuki Orikawa, Hiroki Kato, Koichi Seto, Nobuyoshi Kobayashi, Koji Yoshinaga, Hiroki Hamano, Yuko Hori, Tim Meyer, Mineo Takei
• Journal: Molecular pain (Mol Pain) Vol. 6 Pg. 72 (Oct 28 2010) ISSN: 1744-8069 [Electronic] United States
• PMID: 20979661 (Publication Type: Journal Article)

Chemical References

• 8-sulfocholecystokinin octapeptide
• Benzodiazepinones
• Ephrin-B1
• Interleukin-1beta
• NR2B NMDA receptor
• Receptors, N-Methyl-D-Aspartate
• Z-360
• Receptors, Eph Family
• Devazepide
• Sincalide

Topics

• Animals
• Benzodiazepinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Devazepide (pharmacology)
• Disease Models, Animal
• Ephrin-B1 (genetics, metabolism)
• Extremities
• Ganglia, Spinal (drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Injections
• Interleukin-1beta (administration & dosage, biosynthesis, pharmacology)
• Mice
• Pain (etiology, genetics, pathology)
• Pancreatic Neoplasms (complications, drug therapy)
• Phosphorylation (drug effects)
• Receptors, Eph Family (genetics, metabolism)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Sincalide (analogs & derivatives, pharmacology)
• Up-Regulation (drug effects)