PMID- 24763050
OWN - NLM
STAT- MEDLINE
DCOM- 20150518
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 5
IP  - 4
DP  - 2014 Apr 24
TI  - Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell 
      death.
PG  - e1193
LID - 10.1038/cddis.2014.156 [doi]
AB  - 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.
FAU - Kondratskyi, A
AU  - Kondratskyi A
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Yassine, M
AU  - Yassine M
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Slomianny, C
AU  - Slomianny C
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Kondratska, K
AU  - Kondratska K
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Gordienko, D
AU  - Gordienko D
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Dewailly, E
AU  - Dewailly E
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Lehen'kyi, V
AU  - Lehen'kyi V
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Skryma, R
AU  - Skryma R
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
FAU - Prevarskaya, N
AU  - Prevarskaya N
AD  - Inserm U-1003, Equipe labellisee par la Ligue Nationale contre le cancer, 
      Laboratory of Excellence, Ion Channels Science and Therapeutics, Universite Lille 
      1, Villeneuve d'Ascq, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140424
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Azepines)
RN  - 105637-50-1 (ML 9)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class III Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Autophagy/*drug effects
MH  - Azepines/*pharmacology
MH  - Calcium/metabolism
MH  - Cell Line, Tumor
MH  - Class III Phosphatidylinositol 3-Kinases/metabolism
MH  - Down-Regulation/drug effects
MH  - Homeostasis/drug effects
MH  - Humans
MH  - Hydrogen-Ion Concentration/drug effects
MH  - Lysosomes/*drug effects/ultrastructure
MH  - Male
MH  - Models, Biological
MH  - Phagosomes/drug effects/metabolism/ultrastructure
MH  - Prostatic Neoplasms/metabolism/*pathology/ultrastructure
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4001310
EDAT- 2014/04/26 06:00
MHDA- 2015/05/20 06:00
PMCR- 2014/04/01
CRDT- 2014/04/26 06:00
PHST- 2013/11/08 00:00 [received]
PHST- 2014/02/03 00:00 [revised]
PHST- 2014/02/13 00:00 [accepted]
PHST- 2014/04/26 06:00 [entrez]
PHST- 2014/04/26 06:00 [pubmed]
PHST- 2015/05/20 06:00 [medline]
PHST- 2014/04/01 00:00 [pmc-release]
AID - cddis2014156 [pii]
AID - 10.1038/cddis.2014.156 [doi]
PST - epublish
SO  - Cell Death Dis. 2014 Apr 24;5(4):e1193. doi: 10.1038/cddis.2014.156.