Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single agent in ovarian cancer cells

Abstract

Currently, targeting the autophagic pathway is regarded as a promising new strategy for cancer drug discovery. Here, we screened the North China Pharmaceutical Group Corporation's pure compound library of microbial origin using GFP-LC3B-SKOV3 cells and identified elaiophylin as a novel autophagy inhibitor. Elaiophylin promotes autophagosome accumulation but blocks autophagic flux by attenuating lysosomal cathepsin activity, resulting in the accumulation of SQSTM1/p62 in various cell lines. Moreover, elaiophylin destabilizes lysosomes as indicated by LysoTracker Red staining and CTSB/cathepsin B and CTSD/ cathepsin D release from lysosomes into the cytoplasm. Elaiophylin eventually decreases cell viability, especially in combination with cisplatin or under hypoxic conditions. Furthermore, administration of a lower dose (2 mg/kg) of elaiophylin as a single agent achieves a significant antitumor effect without toxicity in an orthotopic ovarian cancer model with metastasis; however, high doses (8 mg/kg) of elaiophylin lead to dysfunction of Paneth cells, which resembles the intestinal phenotype of ATG16L1-deficient mice. Together, these results provide a safe therapeutic window for potential clinical applications of this compound. Our results demonstrate, for the first time, that elaiophylin is a novel autophagy inhibitor, with significant antitumor efficacy as a single agent or in combination in human ovarian cancer cells, establishing the potential treatment of ovarian cancer by this compound.

Gypenoside L inhibits autophagic flux and induces cell death in human esophageal cancer cells through endoplasm reticulum stress-mediated Ca2+ release

“…However, treatment of Gyp-L resulted in a halt of the execution of autophagy at the stage of autophagosome-lysosome fusion, leading to hallmark accumulation of LC3B-II and p62 (Figure 5). Currently, disruption of the late stages of autophagy might lead to excessive accumulation of autophagic vacuoles containing deleterious undegraded material, which have the potential to turn autophagy into a destructive process [38, 39]. Such inhibition of autophagosome-lysosome fusion has previously been reported for the lysosomal inhibitor CQ, leading to vacuolization and lysosomal swelling as identified here for Gyp-L [40].…”

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

“…Elaiophylin: A natural compound late-stage macroautophagy inhibitor that results in lysosomal membrane permeabilization and decreased cell viability. 1727 See also LMP. Ema (endosomal maturation defective): Ema is required for phagophore expansion and for efficient mitophagy in Drosophila fat body cells.…”

Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer

“…However, patients treated with both HCQ and gemcitabine who met criteria for HCQ response via peripheral blood mononuclear cell LC3 staining demonstrated marked improvement in disease-free and overall survival (Boone et al, 2015). Accordingly, there are several strategies underway to develop new and more potent autophagy inhibitors which may yield better clinical results (Kulkarni et al, 2016;Liu et al, 2011;McAfee et al, 2012;Wang et al, 2015;Zhao et al, 2015).…”