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

Mol Pain. 2010 Oct 28;6:72. doi: 10.1186/1744-8069-6-72.


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.

MeSH terms

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


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