2. Academic Validation
  3. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy

Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy

  • Theranostics. 2018 Jan 1;8(3):830-845. doi: 10.7150/thno.22012.
Pei-Feng Liu 1,  Kun-Lin Tsai 2,  Chien-Jen Hsu 1,  Wei-Lun Tsai 3 4,  Jin-Shiung Cheng 3,  Hsueh-Wei Chang 5 6,  Chung-Wai Shiau 7,  Yih-Gang Goan 8,  Ho-Hsing Tseng 1,  Chih-Hsuan Wu 1,  John C Reed 9,  Lee-Wei Yang 2 10,  Chih-Wen Shu 1
Affiliations

Affiliations

  • 1 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
  • 2 Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu, Taiwan.
  • 3 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
  • 4 School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 5 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 7 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
  • 8 Division of Thoracic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
  • 9 Sanford-Burnham Medical Research Institute, Program on Apoptosis and Cell Death Research, and Conrad Prebys Center for Chemical Genomics, La Jolla, CA, USA.
  • 10 Physics Division, National Center for Theoretical Sciences, Hsinchu 30013, Taiwan.
PMID: 29344310 DOI: 10.7150/thno.22012
Abstract

Background: Tumor cells require proficient Autophagy to meet high metabolic demands and resist chemotherapy, which suggests that reducing autophagic flux might be an attractive route for Cancer therapy. However, this theory in clinical Cancer research remains controversial due to the limited number of drugs that specifically inhibit autophagy-related (ATG) proteins. Methods: We screened FDA-approved drugs using a novel platform that integrates computational docking and simulations as well as biochemical and cellular reporter assays to identify potential drugs that inhibit autophagy-required cysteine proteases of the Atg4 family. The effects of Atg4 inhibitors on Autophagy and tumor suppression were examined using Cell Culture and a tumor xenograft mouse model. Results: Tioconazole was found to inhibit activities of ATG4A and ATG4B with an IC50 of 1.3 µM and 1.8 µM, respectively. Further studies based on docking and molecular dynamics (MD) simulations supported that tioconazole can stably occupy the active site of Atg4 in its open form and transiently interact with the allosteric regulation site in LC3, which explained the experimentally observed obstruction of substrate binding and reduced autophagic flux in cells in the presence of tioconazole. Moreover, tioconazole diminished tumor cell viability and sensitized Cancer cells to autophagy-inducing conditions, including starvation and treatment with chemotherapeutic agents. Conclusion: Tioconazole inhibited Atg4 and Autophagy to enhance chemotherapeutic drug-induced cytotoxicity in cancer Cell Culture and tumor xenografts. These results suggest that the Antifungal drug tioconazole might be repositioned as an Anticancer drug or chemosensitizer.

Keywords

ATG4 and autophagy inhibitory drug; Drug repurposing screen; cancer therapy; docking; molecular dynamics simulations..

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