Overexpression of glioma-associated oncogene 1 (GLI1), which has been characterized as a terminal effector and a target gene of the Hedgehog (Hh) signaling pathway, is associated with the development of cancer. A cellular screen was applied utilizing of a GLI-dependent luciferase reporter in human keratinocyte cells (HaCaT) and identified two terpenoids (1 and 2) and a flavonoid glycoside (5) from Acacia pennata as Hh/GLI inhibitors. Compounds 1, 2, and 5 exhibited selective cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells with no toxic effect on normal cells. This result was consistent with a dose-dependent reduction of the protein levels of antiapoptotic BCL-2 and the tumor suppressor patched 1 protein (PTCH). Additionally, treatment of 1 downregulated mRNA expression of Ptch in PANC1, suggesting that the compound has an inhibitory effect on the transcription of Hh/GLI.

Acute pancreatitis (AP) is associated with significant morbidity and mortality; however, there is no specific treatment for this disease. A novel salivary tripeptide analog, feG, reduces inflammation in several different animal models of inflammation. The aims of this study were to determine whether feG reduced the severity of AP and modifies the expression of pancreatic ICAM-1 mRNA during AP in a mouse model. AP was induced in mice by hourly (x12) intraperitoneal injections of caerulein. A single dose of feG (100 microg/kg) was coadministered with caerulein either at time 0 h (prophylactic) or 3 h after AP induction (therapeutic). Plasma amylase and pancreatic MPO activities and pancreatic ICAM-1 mRNA expression (by RT-PCR) were measured. Pancreatic sections were histologically assessed for abnormal acinar cells and interstitial space. AP induction produced a sevenfold increase in plasma amylase, a tenfold increase in pancreatic MPO activity, and a threefold increase in interstitial space, and 90% of the acinar cells were abnormal. Prophylactic treatment with feG reduced the AP-induced plasma amylase activity by 45%, pancreatic MPO by 80%, the proportion of abnormal acinar cells by 30%, and interstitial space by 40%. Therapeutic treatment with feG significantly reduced the AP-induced abnormal acinar cells by 10% and the interstitial space by 20%. Pancreatic ICAM-1 mRNA expression was upregulated in AP and was reduced by 50% with prophylactic and therapeutic treatment with feG. We conclude that feG ameliorates experimental AP acting at least in part by modulating ICAM-1 expression in the pancreas.

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