An anti-alcoholism drug, disulfiram and copper complex improves radio-resistance of tumor-initiating cells in esophageal squamous cell carcinoma
Background Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity. Methods First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models. Results ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway. Conclusion ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Esophagus - 20(2022), 1 vom: 19. Sept., Seite 134-142 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qian, Li [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Aldehyde dehydrogenase 1 |
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| Anmerkungen: |
© The Author(s) under exclusive licence to The Japan Esophageal Society 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s10388-022-00948-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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OLC2080225731 |
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| 520 | |a Background Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity. Methods First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models. Results ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway. Conclusion ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC. | ||
| 650 | 4 | |a Aldehyde dehydrogenase 1 | |
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| 700 | 1 | |a Murakami, Kentaro |0 (orcid)0000-0002-0115-7726 |4 aut | |
| 700 | 1 | |a Toyozumi, Takeshi |4 aut | |
| 700 | 1 | |a Matsumoto, Yasunori |4 aut | |
| 700 | 1 | |a Otsuka, Ryota |4 aut | |
| 700 | 1 | |a Sekino, Nobufumi |4 aut | |
| 700 | 1 | |a Endo, Satoshi |4 aut | |
| 700 | 1 | |a Kinoshita, Kazuya |4 aut | |
| 700 | 1 | |a Sasaki, Takuma |4 aut | |
| 700 | 1 | |a Matsubara, Hisahiro |4 aut | |
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