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.
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.
Orikawa
Yuki
Y
Central Research Laboratories, Zeria Pharmaceutical Co,, Ltd,, 2512-1 Numagami, Oshikiri, Kumagaya-shi, Saitama, Japan. yuki-orikawa@zeria.co.jp
Kato
Hiroki
H
Seto
Koichi
K
Kobayashi
Nobuyoshi
N
Yoshinaga
Koji
K
Hamano
Hiroki
H
Hori
Yuko
Y
Meyer
Tim
T
Takei
Mineo
M
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D020109:Devazepide / Q000494:pharmacology; D004195:Disease Models, Animal; D036387:Ephrin-B1 / Q000235:genetics* / Q000378:metabolism; D005121:Extremities; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007267:Injections; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000096:biosynthesis* / Q000494:pharmacology; D051379:Mice; D010146:Pain / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000150:complications / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
C090019:8-sulfocholecystokinin octapeptide; D001570:Benzodiazepinones; D036387:Ephrin-B1; D053583:Interleukin-1beta; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C528831:Z-360; D036081:Receptors, Eph Family; D020109:Devazepide; D012844:Sincalide