期刊
ACTA PHARMACEUTICA SINICA B
卷 12, 期 7, 页码 3085-3102出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2022.01.018
关键词
Econazole; Autophagy; PDAC; ATF3; AKT; Organoid; Trametinib; Therapy
资金
- Guangdong Basic and Applied Basic Research Foundation (China) [2019B030302012]
- National Key R&D Program of China [2020YFA0509400, 2020YFC2002705]
- NSFC (China) [81821002, 81790251, 82130082]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (China) [ZYJC21042]
Econazole (ECON), an antifungal compound, has been found to inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) by promoting autophagy initiation and blocking lysosome biogenesis. It also exhibits synergistic effects with trametinib on PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxy-chloroquine has shown promise. However, current realization is impeded by its suboptimal use and un-predictable 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/mamma-lian 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. 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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