Elaiophylin, A Novel Autophagy Inhibitor,Exerts Anti-tumor Activity As A Single-agent In Ovarian Cancer Cells

Autophagy, a conserved eukaryotic catabolic process that leads to the autophagosomic-lysosomal degradation of damaged organelles and long-lived proteins, is crucial to maintain cellular homeostasis and cell survival under stressful condition. Dysfunction of autophagy has been associated with a variety of human diseases including infectious diseases, cardiovascular disease, neurodegenerative diseases, and especially cancer. 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-SKOV3cells 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 SQSTMl/p62in 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 (2mg/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 (8mg/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.