Theranostics 2018; 8(3):830-845. doi:10.7150/thno.22012 This issue Cite

Research Paper

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

Pei-Feng Liu1*, Kun-Lin Tsai2*, Chien-Jen Hsu1*, Wei-Lun Tsai3,4, Jin-Shiung Cheng3, Hsueh-Wei Chang5,6, Chung-Wai Shiau7, Yih-Gang Goan8, Ho-Hsing Tseng1, Chih-Hsuan Wu1, John C. Reed9#, Lee-Wei Yang2,10✉, Chih-Wen Shu1✉

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.
* Co-first authors
# Present address: Roche. Basel, Switzerland

Citation:
Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, Reed JC, Yang LW, Shu CW. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics 2018; 8(3):830-845. doi:10.7150/thno.22012. https://www.thno.org/v08p0830.htm
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Abstract

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


Citation styles

APA
Liu, P.F., Tsai, K.L., Hsu, C.J., Tsai, W.L., Cheng, J.S., Chang, H.W., Shiau, C.W., Goan, Y.G., Tseng, H.H., Wu, C.H., Reed, J.C., Yang, L.W., Shu, C.W. (2018). Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics, 8(3), 830-845. https://doi.org/10.7150/thno.22012.

ACS
Liu, P.F.; Tsai, K.L.; Hsu, C.J.; Tsai, W.L.; Cheng, J.S.; Chang, H.W.; Shiau, C.W.; Goan, Y.G.; Tseng, H.H.; Wu, C.H.; Reed, J.C.; Yang, L.W.; Shu, C.W. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics 2018, 8 (3), 830-845. DOI: 10.7150/thno.22012.

NLM
Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, Reed JC, Yang LW, Shu CW. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics 2018; 8(3):830-845. doi:10.7150/thno.22012. https://www.thno.org/v08p0830.htm

CSE
Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, Reed JC, Yang LW, Shu CW. 2018. Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy. Theranostics. 8(3):830-845.

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