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

Acta Pharmaceutica Sinica B 2022年第7期12卷 3085-3102页

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 Department of Abdominal Oncology West China Hospital of Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China Department of Pancreatic Surgery West China Hospital of Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of HopeBiomedical Research CenterMonroviaCA 91016USA Department of Oncology the First Affiliated HospitalXi’an Jiaotong UniversityXi’an 710061China

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

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Drug repurposing identifies Econazole as a novel neuroprotective agent that activates autophagy/mitophagy in Parkinson disease models

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中国药理学与毒理学杂志 2019年第10期 780-780页

作者： ZHEN Yong-qi ZHAO Yu-qian FU Lei-lei LIU Bo School of Life Science and Engineering Southwest Jiaotong University State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University

OBJECTIVE To discover new drugs for Parkinson disease(PD), we sought to focus on its pathogenesis. Autophagy is involved in the pathogenesis of PD, and recent accumulating evidence has revealed that defects in autophagy have implications for potential therapy.To our knowledge, PD treatment with conventional drugs may result in some serious adverse reactions; therefore,discovery of more autophagic inducers will be a possible strategy. METHODS The mechanisms of Econazole induced cytoprotective autophagy were investigated by electron microscopy, fluorescence microscopy, Western blotting, co-immunoprecipitation assay, si RNA and GFP-LC3 plasmid transfections. The therapeutic effect of Econazole was determined by MPTP-mouse model, including behavioral tests, the levels of dopamine and its derivatives, as well as immunofluorescence and Western blotting. RESULTS Econazole could trigger autophagy by the ULK complex and ATG5-dependent pathways in SH-SY5 Y cells. Econazole was also found to induce mitophagy via the activation of Parkin-PINK1 pathway.Interestingly, Econazole had a cytoprotective autophagic effect by ameliorating MPP+-induced cell death as well as reducing expression of α-synuclein inα-synu A53 T SH-SY5 Y cells. Moreover, we demonstrated that Econazole had a neuroprotective effect on mouse and zebrafish models of PD, respectively. Combined with microarray analyses of mouse brain tissues, Econazole could inhibit apoptosis by DLK-JNK pathway, and activated autophagy by Ambra1-Beclin1-Vps34 complex. CONCLUSION Econazole, an old anti-fungal drug, would be utilized as a novel neuroprotective agent that activates autophagy/mitophagy for the future PD therapeutics.

关键词： autophagy Parkinson disease Econazole ULK complex mitophagy SH-SY5Y cell α-synuclein

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Separation of chiral drugs with sulfobutylether-β-cyclodextrin bycapillary zone electrophoresis

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Chinese Chemical Letters 1999年第1期10卷 39-42页

作者： Jun Ying LIU Yi Yang DONG Tian Song WANG Hu Wei LIU Al Jin HUANG yi Liang SUNI Zeng Pei SUN(Department of Chemistry． Peking University． Beijing 100871)(Natlonal Institute for the Control of Pharmaceutical and Biological Products，Beijing 100050) Department of Chemistry Peking University Beijing 100871 China Natl. Inst. Contr. Pharmaceutical B. Beijing 100050 China

Sulfobutylether－β－cyclodextrin（SBE－β－CD）was used as a chiral selector tor separatingten chlral drugs with resolution 1．2 by capillary zone electrophoresls（CZE）， The backgroundelectrolylc solution comprised of 120 mmol／L Britton－Robinson buffer（BRB） containing1 ～10mmol／L SBE－β－CD with the pH value adjusted from 5．0－6．8． Five of the drugs were better resolvedthan those previously reported with neutral CDs．

关键词： Chiral separation sulfobutylether-β-cyclodextrin capillary zone electrophoresis anlsodamlne bencynonate Econazole esmolol glycopynonate lobeline methoxamine phenylephrine plnacidll terazosin

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