PMID- 31310755
OWN - NLM
STAT- MEDLINE
DCOM- 20200128
LR  - 20200128
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 859
DP  - 2019 Sep 15
TI  - Comparative analysis of cell death mechanisms induced by lysosomal autophagy 
      inhibitors.
PG  - 172540
LID - S0014-2999(19)30492-3 [pii]
LID - 10.1016/j.ejphar.2019.172540 [doi]
AB  - We performed a comparative analysis of molecular cytotoxic mechanisms of 
      lysosomal autophagy inhibitors bafilomycin A1, chloroquine, and ammonium chloride 
      in B16 mouse melanoma cells. All agents caused oxidative stress, mitochondrial 
      depolarization, and caspase-dependent apoptotic death, which was not affected by 
      genetic inactivation of autophagy. Cathepsin inhibition reduced only the 
      cytotoxicity of chloroquine, indicating its ability to cause lysosomal membrane 
      permeabilization. Bafilomycin reduced the mRNA levels of anti-apoptotic Bcl-2, 
      while chloroquine and ammonium chloride increased the mRNA expression of 
      pro-apoptotic Pten and Puma, as well as anti-apoptotic Bcl-xL. Ammonium chloride 
      additionally increased the mRNA expression of pro-apoptotic Bim and p53. All 
      three agents decreased the activity of mechanistic target of rapamycin (mTOR) and 
      increased the activation of p38 mitogen-activated protein kinase (MAPK). 
      Chloroquine and ammonium chloride additionally stimulated the phosphorylation of 
      extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), 
      respectively, while only bafilomycin increased the phosphorylation of the energy 
      sensor AMP-activated protein kinase (AMPK). mTOR activator leucine did not affect 
      the cytotoxicity of lysosomal inhibitors. p38 MAPK inhibitor SB203580 reduced the 
      cytotoxicity of bafilomycin but increased that of chloroquine and ammonium 
      chloride. The pharmacological inhibition of ERK1/2, JNK, and AMPK potentiated the 
      cytotoxicity of chloroquine, ammonium chloride, and bafilomycin, respectively. 
      The observed mechanistic differences were associated with antagonistic 
      interactions of lysosomal inhibitors in B16 cell killing. In conclusion, all 
      investigated lysosomal inhibitors cause autophagy-independent mitochondrial 
      dysfunction and apoptotic death, but differ in the ability to affect lysosomal 
      permeabilization, balance between pro- and anti-apoptotic molecules of Bcl-2 
      family, and MAPK/AMPK signaling.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Stamenkovic, Marina
AU  - Stamenkovic M
AD  - Institute of Microbiology and Immunology, School of Medicine, University of 
      Belgrade, Dr. Subotica 1, 11000, Belgrade, Serbia.
FAU - Janjetovic, Kristina
AU  - Janjetovic K
AD  - Institute for Biological Research "Sinisa Stankovic", University of Belgrade, 
      Despota Stefana Blvd. 142, 11000, Belgrade, Serbia.
FAU - Paunovic, Verica
AU  - Paunovic V
AD  - Institute of Microbiology and Immunology, School of Medicine, University of 
      Belgrade, Dr. Subotica 1, 11000, Belgrade, Serbia.
FAU - Ciric, Darko
AU  - Ciric D
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000, Belgrade, Serbia.
FAU - Kravic-Stevovic, Tamara
AU  - Kravic-Stevovic T
AD  - Institute of Histology and Embryology, School of Medicine, University of 
      Belgrade, Visegradska 26, 11000, Belgrade, Serbia.
FAU - Trajkovic, Vladimir
AU  - Trajkovic V
AD  - Institute of Microbiology and Immunology, School of Medicine, University of 
      Belgrade, Dr. Subotica 1, 11000, Belgrade, Serbia. Electronic address: 
      vladimir.trajkovic@med.bg.ac.rs.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20190713
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Antineoplastic Agents)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Autophagy/*drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Lysosomes/*drug effects/*pathology
MH  - MAP Kinase Signaling System/drug effects
MH  - Melanoma, Experimental/*pathology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Oxidative Stress/drug effects
OTO - NOTNLM
OT  - AMPK
OT  - Apoptosis
OT  - Autophagy inhibitors
OT  - Bcl-2
OT  - Lysosomes
OT  - MAP kinases
EDAT- 2019/07/17 06:00
MHDA- 2020/01/29 06:00
CRDT- 2019/07/17 06:00
PHST- 2019/02/28 00:00 [received]
PHST- 2019/06/18 00:00 [revised]
PHST- 2019/07/12 00:00 [accepted]
PHST- 2019/07/17 06:00 [pubmed]
PHST- 2020/01/29 06:00 [medline]
PHST- 2019/07/17 06:00 [entrez]
AID - S0014-2999(19)30492-3 [pii]
AID - 10.1016/j.ejphar.2019.172540 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2019 Sep 15;859:172540. doi: 10.1016/j.ejphar.2019.172540. Epub 
      2019 Jul 13.