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.Howe...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.展开更多
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 compris...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．展开更多
基金funded by Guangdong Basic and Applied Basic Research Foundation(2019B030302012,China)National Key R&D Program of China(2020YFA0509400 and 2020YFC2002705)+1 种基金NSFC(81821002,81790251 and 82130082,China)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21042,China)。
文摘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.
文摘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．
