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Autophagy. 2015;11(10):1849-63. doi: 10.1080/15548627.2015.1017185.

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

Author information

1
a Cancer Biology Research Center; Tongji Hospital; Tongji Medical College, Huazhong University of Science and Technology ; Wuhan , Hubei , China.
2
b NCPC New Drug Research and Development Co.Ltd, North China Pharmaceutical Group Corporation ; Shijiazhuang , China.
3
c Shanghai Biomabs Pharmaceutical Co. Ltd ; Shanghai , China.

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.

KEYWORDS:

antitumor; autophagy; cell death; elaiophylin; natural compound; ovarian cancer

PMID:
25893854
PMCID:
PMC4824600
DOI:
10.1080/15548627.2015.1017185
[Indexed for MEDLINE]
Free PMC Article

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