American Association for Cancer Research
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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.



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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.

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