title: 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.
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Zhao
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Lai
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Li
authors.initials: L
authors.lastname: Meng
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Daowen
authors.initials: D
authors.lastname: Wang
authors.affiliation: b NCPC New Drug Research and Development Co.Ltd, North China Pharmaceutical Group Corporation ; Shijiazhuang , China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: b NCPC New Drug Research and Development Co.Ltd, North China Pharmaceutical Group Corporation ; Shijiazhuang , China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lu
authors.affiliation: c Shanghai Biomabs Pharmaceutical Co. Ltd ; Shanghai , China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; C033279:elaiophylin
keywords: antitumor; autophagy; cell death; elaiophylin; natural compound; ovarian cancer