Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61.

Apratoxin A is a natural product with potent anti-proliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biological activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anti-cancer drug. Here we describe a detailed pathological analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing co-translational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well-defined. By using a 3H labeled apratoxin A probe and specific Sec61α/β antibodies, we identified that the Sec61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure.