RESUMO
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 (mTOR) 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.
RESUMO
Objective Toinvestigatetheeffectoftranscatheterarterialchemoembolization(TACE)combinedwithinterferon(IFN)adju-vanttherapyinthetreatmentofadvancedprimarylivercancer,andtoprovidenewideasforadjuvanttherapiesafterTACE.Methods The databases including Cochrane Library,PubMed,Medline,Embase,CNKI,Wanfang Data,and VIP were searched to obtain all articles pub-lished before January 2015,and the randomized controlled trials (RCTs)about the comparison between TACE combined with IFN and TACE alone published in journals at home and abroad were included.Quality assessment and data extraction were performed for these articles,and Revman5.1softwarewasappliedforthemeta-analysis.Results Atotalof6RCTswereincluded,consistingof311patientsintheIFN adjuvant therapy group and 308 patients in the placebo group.The results of the meta -analysis showed that compared with the placebo group,the IFN adjuvant treatment group had significantly lower 1 -,2-,and 3-year recurrence rates and a significantly higher 1 -year survivalrate(P=0.006,0.002,0.002,and0.030).Conclusion IFNadjuvanttherapycanreducetheriskoflivercancerrecurrence after TACE and improve the patients′survival rate.
