Activation of the nuclear transcription factor-kappaB (NF-κB) has been implicated in the progression and metastasis of pancreatic cancer. This study was designed to evaluate the effects of a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) in the inhibition of liver metastasis of pancreatic cancer in a clinical liver metastasis-simulating mouse model in which cancer cells were intra-portal injected via small laparotomy. Moreover, synergistic effect of combination therapy with DHMEQ and gemcitabine was investigated. Male BALB/c nude mice were xenografted with intra-portal vein injection of AsPC-1. Mice were divided into four groups; 1) positive control (PC), without any treatment, 2) gemcitabine treated group (GEM), 3) DHMEQ treated group, and 4) combined treatment group (GEM+DHMEQ). Mice were fed for four weeks, and the number of liver metastases, induction of apoptosis and angiogenesis in metastasis foci were investigated after sacrifice. The number of liver metastases decreased significantly in the GEM group, DHMEQ group and GEM+DHMEQ group when compared with the PC group. Significant inductions of apoptosis were revealed in the GEM group and DHMEQ group compared to the PC group, in which apoptotic bodies in metastasis sections were counted by using the TUNEL method. Moreover, in the DHMEQ+GEM group, synergistic effect of combination therapy was observed in induction of apoptosis. Tumor vessels were indentified by immunohistochemical staining of tumor metastasis sections with antibody against CD31. There was a large reduction in the number of CD31-positive vessels in the tumor of DHMEQ or/and GEM-treated mice as compared with control group. Gene expression in metastasis sites was investigated by quantitative RT-PCR. DHMEQ down-regulated IL-8 and MMP-9 remarkably, while gemcitabine down-regulated VEGF moderately. The differences in down-regulated target genes and mechanisms of anti-tumor effects between DHMEQ and gemcitabine point towards the validity of combination therapy with DHMEQ and gemcitabine.

In our intra-portal vein injection model, which mimics liver metastasis of pancreatic cancer very well, DHMEQ exhibited anti-tumor effect by inhibiting angiogenesis, invasiveness of tumor cells, and induction of apoptosis. Moreover, when DHMEQ and gemcitabine were administered simultaneously, our result suggested the possibility of a synergistic effect. DHMEQ is lipophilic agent and insoluble in common solvents. Thus, DHMEQ might be a potent drug for the treatment of pancreatic cancer, although in the case of clinical application, some difficulties remain to be solved, such as a dissolution method and an administration route.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4058.