Preclinical Development of a Pharmacologic Agent for the Treatment of Recurrent Acute Pancreatitis

Abstract

Chronic pancreatitis (CP) is an irreversible disease process defined by acinar cell necrosis, inflammation and fibrosis. With disease progression, patients develop pancreatic insufficiency secondary to the destruction of functional pancreatic tissue and its replacement with scarring. Patients with CP have a poor quality of life, and their treatment options are limited to supportive care and symptom palliation. There are currently no drugs on the market directly targeting the pathogenesis of CP. The objective of this research is to develop a pharmacologic agent for the treatment of recurrent acute pancreatitis (RAP), thereby limiting progression to CP. Apigenin is a natural compound with known anti-inflammatory, anti-proliferative, and pro-apoptotic properties. In a mouse model of RAP, the natural compound, apigenin, protected the pancreas from histologic damage while minimizing fibrosis. It was hypothesized that apigenin minimized the sequelae of RAP by inhibiting the inflammatory and fibrotic response to recurrent injury. Parathyroid hormone related protein (PTHrP) is a pro-inflammatory and pro-fibrotic mediator of acute and CP. The first aim was to identify PTHrP-related mechanisms by which apigenin limits inflammation in acinar cells. Apigenin reduced activation of the MAPK/ERK and NF-κB pathways, leading to suppression of PTHrP P3 promoter activity and IL-6 transcription. The second aim was to determine how apigenin limits pancreatic stellate cell (PSC)-mediated fibrosis. Apigenin inhibited PSC proliferation, induced PSC death, reduced PSC transcription of extracellular matrix proteins collagen and fibronectin, proliferative cofactor PCNA, and cytokines TGF-β, IL-6, and IL-8. The last aim was to develop apigenin-like compounds with more favorable drug-like properties. Analogs with improved aqueous solubility were tested in vitro and in vivo for increased potency. Analog HJC 05-61 was more potent than apigenin at limiting PSC viability and inducing PSC apoptosis. In a proof-of-concept RAP mouse study, apigenin derivatives were as effective as apigenin in preserving pancreatic architecture and limiting fibrosis. Thus, apigenin and analogs protect the pancreas during RAP by limiting the pro-inflammatory and pro-fibrotic response to pancreatic injury. This is in part mediated through down-regulation of PTHrP and PSC activity, both of which participate in autocrine and paracrine signaling that perpetuates pancreatitis.