Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death.

Abstract:

:The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Kondratskyi A,Yassine M,Slomianny C,Kondratska K,Gordienko D,Dewailly E,Lehen'kyi V,Skryma R,Prevarskaya N

doi

10.1038/cddis.2014.156

subject

Has Abstract

pub_date

2014-04-24 00:00:00

pages

e1193

issn

2041-4889

pii

cddis2014156

journal_volume

5

pub_type

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