Background: Obesity is one of the principal causes of metabolic syndrome. Results: A novel PPAR␣ agonist/␥ antagonist, Z-551, ameliorates obesity, insulin resistance, and impairment of glucose and lipid metabolisms in mice. Conclusion: Z-551 might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders. Significance: A novel combination of PPAR␣ agonist/␥ antagonist is effective to improve obesity and obesity-related metabolic disorders.

BackgroundZ-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.ResultsIn 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.ConclusionsWe 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.

Z-360, calcium bis[(R)-(Ϫ)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]-[1,4]diazepin-3-yl}ureido]benzoate], is a novel orally active cholecystokinin (CCK)-2/gastrin receptor antagonist that is being developed for use in combination with the chemotherapy agent gemcitabine for the treatment of pancreatic adenocarcinoma.1,2) Our previous studies show that the oral administration of Z-360 significantly inhibited the growth of subcutaneous xenograft of human pancreatic tumor cells in mice 2,3) and that Z-360 combined with gemcitabine inhibited pancreatic tumor growth and prolonged survival of a pancreatic carcinoma orthotopic xenograft model. 1)It is known that gastrin stimulates the survival or proliferation of normal cells and gastric, 4,5) colorectal, 5) or pancreatic cancer cells 6,7) by the endocrine, autocrine, and paracrine mechanisms. Watson et al. report that cancer cells overexpress the gastrin gene and are sensitive to the trophic effects of gastrin. 8) A recent study revealed that the intracellular signaling pathway involved in the activation of the CCK-2/gastrin receptor leads to carcinogenesis. 9) Moreover, studies on transgenic mice overexpressing the gastrin or CCK-2/gastrin receptors show that gastrin is involved in the development of gastric and pancreatic tumors. 10,11) In the pre-clinical studies of CCK-2/gastrin receptor antagonists, the role of gastrin and the CCK-2/gastrin receptor in human pancreatic carcinogenesis was investigated in vitro by using human pancreatic carcinoma cell lines 12) and in vivo by using xenograft models.6) CCK-2/gastrin receptor antagonists such as L-365260 6,13) inhibited the growth of pancreatic carcinoma-derived cell lines in these models 6,7) ; the results suggesting treatment with a CCK-2/gastrin receptor antagonist is useful for patients with pancreatic cancer expressing this receptor. In fact, the efficacy of some CCK-2/gastrin receptor antagonists for advanced pancreatic carcinoma was evaluated in several clinical trials. Gastrazole (JB95008), a CCK-2/gastrin receptor antagonist, significantly prolonged survival compared with placebo, 14,15) and this observation provides evidence that the inhibition of gastrin-dependent pathophysiological changes can be effective therapy for pancreatic carcinoma.Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide and is overexpressed in tumor tissues of patients with some cancers such as pancreatic cancer or nonsmall lung cancer. [16][17][18] Many studies show that the expression of VEGF is correlated with the survival of patients with pancreatic cancer 19,20) and that VEGF is an important prognostic factor for the survival of patients with pancreatic cancer. VEGF is strongly induced by hypoxia, which often occurs in the tumor microenvironment.21) It is now becoming clear that the microenvironment has an influence on both tumorigenesis and metastasis, and VEGF is very important in this microenvironment.In this study, we investigated factors related to survival, in...

Lymphatic metastasis is common in advanced-stage carcinoma and is associated with a poor prognosis. However, few effective treatments to inhibit it are available. Z-100 is an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B that contains polysaccharides such as arabinomannan and mannan. Here, we investigated the inhibitory effect of Z-100 on spontaneous lymphatic metastasis. C57BL/6N mice injected subcutaneously with B16-BL6 melanoma cells in the right hind footpad were administered Z-100 subcutaneously in the right inguinal region on a daily basis. On day twenty-one after the injection, the right inguinal lymph nodes were excised, and the extent of metastasis, the number of immune cells, and the amount of granzyme B protein in the lymph nodes were examined. We also investigated the combined effect of Z-100 and irradiation in this model. Results showed that Z-100 reduced number of animals with metastasis, with respective metastasis rates of 85.7%, 42.9%, 7.1% and 0.0% in saline, 0.1 mg/kg Z-100, 1 mg/kg Z-100 and 10 mg/kg Z-100 group. Further, mice that had been given Z-100 were found to have more immune cells and granzyme B protein in the lymph nodes than control mice. The combination of low dose Z-100 and irradiation also inhibited spontaneous lymph node metastases. These findings suggest that Z-100 may be beneficial in preventing lymphatic metastasis by enhancing the immune response.Key words lymph node metastasis; B16-BL6 melanoma cell; non-specific immunotherapy; radiation Metastasis is the main cause of death in advanced-stage cancer patients and occurs through three major routes: hematogenous, lymphogenous, and transcoelomic spread.1,2) Lymphatic metastasis in particular is common in advanced-stage carcinoma and is generally associated with a poor prognosis. Although the influence of lymphatic metastasis on prognosis is thoroughly understood, effective treatments to inhibit it remain lacking. 3,4) Lymph node dissection is frequently performed to treat or prevent (or both) lymph node metastasis in several types of cancer. These procedures are limited to early-stage cancer patients, however, and their efficacy has been questioned. 5,6) Chemotherapy and lymphangiogenesis inhibitors are administered in lieu of surgery to inhibit lymphatic metastasis, [7][8][9] but these drugs have limited efficacy due to their toxicity and poor bioavailability. Specifically, conventional chemotherapy cannot be delivered to the lymphatic system effectively without dose-limiting toxicity, requiring drug delivery systems such as a liposome-based delivery system. 9,10) Therefore, novel therapeutics are needed for the use in treating cancer patients with lymphatic metastasis.Immunotherapeutic approaches have been shown to inhibit lymphatic metastasis in animal models, indicating the potential of immunotherapy as treatment for lymphatic metastasis in humans.11-13) Z-100 is a hot-water extract of Mycobacterium tuberculosis strain Aoyama B and contains polysaccharides such as arabinomannan and mannan.14) Z-100 h...