Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma  

作　　者：Ningna Weng Siyuan Qin Jiayang Liu Xing Huang Jingwen Jiang Li Zhou Zhe Zhang Na Xie Kui Wang Ping Jin Maochao Luo Liyuan Peng Edouard C.Nice Ajay Goel Suxia Han Canhua Huang Qing Zhu 

机构地区：[1]Department of Abdominal Oncology,West China Hospital of Sichuan University,Chengdu 610041,China [2]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,West China School of Basic Medical Sciences&Forensic Medicine,Sichuan University,Collaborative Innovation Center for Biotherapy,Chengdu 610041,China [3]Department of Pancreatic Surgery,West China Hospital of Sichuan University,Chengdu 610041,China [4]Department of Biochemistry and Molecular Biology,Monash University,Clayton,VIC 3800,Australia [5]Department of Molecular Diagnostics and Experimental Therapeutics,Beckman Research Institute of City of Hope,Biomedical Research Center,Monrovia,CA 91016,USA [6]Department of Oncology,the First Affiliated Hospital,Xi’an Jiaotong University,Xi’an 710061,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第7期3085-3102,共18页药学学报（英文版）

基　　金：funded by Guangdong Basic and Applied Basic Research Foundation(2019B030302012,China);National Key R&D Program of China(2020YFA0509400 and 2020YFC2002705);NSFC(81821002,81790251 and 82130082,China);1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21042,China)。

摘　　要：Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

关 键 词：ECONAZOLE AUTOPHAGY PDAC ATF3 AKT Organoid Trametinib Therapy 

分 类 号：R979.1[医药卫生—药品]