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

Abstract

Apratoxin A is a natural product with potent antiproliferative 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 biologic 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 anticancer drug. Here, we describe a detailed pathologic 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 cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a (3)H-labeled apratoxin A probe and specific Sec 61α/β antibodies, we identified that the Sec 61 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. Mol Cancer Ther; 15(6); 1208-16. ©2016 AACR.

• Authors: Kuan-Chun Huang, Zhihong Chen, Yimin Jiang, Sandeep Akare, Donna Kolber-Simonds, Krista Condon, Sergei Agoulnik, Karen Tendyke, Yongchun Shen, Kuo-Ming Wu, Steven Mathieu, Hyeong-Wook Choi, Xiaojie Zhu, Hajime Shimizu, Yoshihiko Kotake, William H Gerwick, Toshimitsu Uenaka, Mary Woodall-Jappe, Kenichi Nomoto
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 6 Pg. 1208-16 (06 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27196783 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Depsipeptides
• SEC Translocation Channels
• apratoxin A

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Depsipeptides (pharmacokinetics, toxicity)
• Humans
• MCF-7 Cells
• Maximum Tolerated Dose
• Mice
• Neoplasm Transplantation
• Neoplasms (drug therapy, metabolism)
• Organ Specificity
• Pancreas (drug effects)
• Protein Binding
• Rats
• SEC Translocation Channels (metabolism)