Apratoxin‐A Induces Pancreatic Toxicity

Abstract

Objective of this study was to characterize toxicity induced by Apratoxin‐A, a marine cyanobacterium derived natural product with anti‐cancer activity. In mice, severe weight loss in absence of decreased food consumption or activity was seen, and defined the maximal tolerated dose (MTD). Histopathological evaluation revealed pancreatic atrophy with widespread apoptosis, cell loss and small/collapsed lobules but without cell necrosis, neutrophilic inflammation and fibrosis, and thus mediated by an apoptotic rather than a necrotic mechanism. A tissue bio‐distribution study showed accumulation of Apratoxin‐A in pancreas and mandibular salivary gland at a very high concentration compared to liver, kidney and plasma; however, histologically, the salivary gland acinar cells had decreased cytoplasm but no apoptosis or cell loss. The selective apoptosis and cell loss in pancreas may be due to highly sensitive pro‐apoptotic safeguarding mechanism(s) in the pancreatic exocrine cells to prevent leakage of pancreatic enzymes and avoid severe tissue damage, inflammation and fibrosis. There was no cytotoxicity present in the intestine up to the MTD dose indicating that the Apratoxin‐A activity does not target rapidly dividing cells, but instead acts through functional inhibition of a target protein, likely Sec61, an ER protein important in secretory protein translocation that is expressed at significantly high levels in exocrine glands: pancreas, salivary gland and prostate. In summary, Apratoxin‐A shows selective pancreatic toxicity that is associated with high bio‐distribution to pancreas as well as susceptibility of pancreas for functional inhibition of Apratoxin‐A target protein.