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Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single
agent in ovarian cancer cells
#MMPMID25893854
Zhao X
; Fang Y
; Yang Y
; Qin Y
; Wu P
; Wang T
; Lai H
; Meng L
; Wang D
; Zheng Z
; Lu X
; Zhang H
; Gao Q
; Zhou J
; Ma D
Autophagy
2015[]; 11
(10
): 1849-63
PMID25893854
show ga
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.
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