title: 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.affiliation: Eisai Inc., Andover, Massachusetts. kuan-chun_huang@eisai.com.
authors.forename: Kuan-Chun
authors.initials: KC
authors.lastname: Huang
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Akare
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Donna
authors.initials: D
authors.lastname: Kolber-Simonds
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Krista
authors.initials: K
authors.lastname: Condon
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Sergei
authors.initials: S
authors.lastname: Agoulnik
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Tendyke
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Kuo-Ming
authors.initials: KM
authors.lastname: Wu
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Steven
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Hyeong-Wook
authors.initials: HW
authors.lastname: Choi
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Eisai Co. Ltd., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Eisai Co. Ltd., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kotake
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California.
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.affiliation: Eisai Inc., Exton, Pennsylvania.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Mary
authors.initials: M
authors.lastname: Woodall-Jappe
authors.affiliation: Eisai Inc., Andover, Massachusetts.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D061986:MCF-7 Cells; D020714:Maximum Tolerated Dose; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009928:Organ Specificity; D010179:Pancreas / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D000069816:SEC Translocation Channels / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D000069816:SEC Translocation Channels; C442201:apratoxin A