Development of novel therapeutic strategies targeting esophageal tumor-initiating cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09211
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Chiba University
• Principal Investigator: MURAKAMI KENTARO 千葉大学, 医学部附属病院, 講師 (40436382)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 食道癌

Outline of Final Research Achievements

Methods: First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines. 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.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

近年ドラッグリポジショニングの概念が広まっている。本研究では将来の臨床応用を視野に入れ、断酒薬でALDH阻害作用があるdisulfiramに焦点を当てた。 disulfiramは、Antabuseの商品名で販売されており、1951年に米国食品医薬品局によってアルコール使用障害の治療薬として承認された最初の医薬品である。disulfiramは抗がん剤として注目されており、いくつかの臨床試験が実施されているが、食道扁平上皮癌に関してはその有用性は十分に検証されていない。本研究では、disulfiramによるALDH1阻害が放射線抵抗性を改善することが示され、 臨床応用への基盤となる結果が得られた。