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Supplemental Figures S1-S6 and Table S1 from Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61

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posted on 2023-04-03, 14:48 authored by 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

Figure S1. Synthesis of [3H]apratoxin A. Figure S2. Synthesis of C.18-epi-apratoxin A. Figure S3. Apratoxin A in vitro IC50 against panels of human cancer cell lines. Table S1. Summary table for in vivo efficacy studies. Figure S4. Apratoxin A concentration kinetics in plasma and various tissues in A549 human lung cancer xenograft tumor-bearing mice after a single IV dose (1 mg/kg). Figure S5. Apratoxin A and HUN-7293 have different binding sites on the Sec61 complex. Figure S6. Sec61α and Sec61β protein expression levels among different cell lines.

Funding

NIH

International Cooperative Biodiversity Groups Program

History

ARTICLE 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 3H-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.