PMID- 25637161
OWN - NLM
STAT- MEDLINE
DCOM- 20150710
LR  - 20211203
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 360
IP  - 1
DP  - 2015 Apr 28
TI  - Dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor 
      NVP-BEZ235 synergizes with chloroquine to induce apoptosis in embryonal 
      rhabdomyosarcoma.
PG  - 1-9
LID - S0304-3835(14)00759-9 [pii]
LID - 10.1016/j.canlet.2014.12.016 [doi]
AB  - Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target 
      of rapamycin (mTOR) pathway has been reported for rhabdomyosarcoma (RMS) and is 
      implicated in survival of tumor cells as well as therapeutic resistance. In the 
      present study, we searched for combination therapies with the dual PI3K/mTOR 
      inhibitor NVP-BEZ235 (BEZ235) in RMS. Here, we identify a synthetic lethal 
      interaction of BEZ235 together with the lysosomotropic agent chloroquine (CQ), 
      which is effective against embryonal rhabdomyosarcoma (ERMS). BEZ235 and CQ at 
      subtoxic concentrations synergize to induce apoptosis in ERMS cells, as confirmed 
      by calculation of combination index (CI). BEZ235 and CQ cooperate to activate 
      caspase-9, -3 and -8, which is crucial for apoptosis induction given that the 
      broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone 
      (zVAD.fmk) blocks BEZ235/CQ-induced apoptosis. Additionally, pharmacological 
      inhibition of lysosomal enzymes significantly reduces BEZ235/CQ-induced 
      apoptosis, indicating concomitant activation of the lysosomal compartment. 
      Importantly, BEZ235/CQ-induced apoptosis is significantly inhibited by 
      antioxidants, implying that increased oxidative stress contributes to 
      BEZ235/CQ-induced cell death. Importantly, our molecular studies reveal that 
      BEZ235/CQ-induced apoptosis is mediated by cooperative downregulation of the 
      antiapoptotic BCL-2 family protein MCL-1, since stabilization of MCL-1 by 
      expression of a non-degradable MCL-1 phospho-defective mutant significantly 
      decreases BEZ235/CQ-induced apoptosis. Also, overexpression of antiapoptotic 
      BCL-2 leads to a significant reduction of BEZ235/CQ-induced apoptosis, 
      emphasizing that an intact mitochondrial pathway of apoptosis is required for 
      BEZ235/CQ-induced cell death. This identification of a synthetic lethality of 
      BEZ235 and CQ has important implications for the development of molecular 
      targeted therapies for RMS.
CI  - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved.
FAU - Hugle, Manuela
AU  - Hugle M
AD  - Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 
      Komturstr. 3a, 60528 Frankfurt, Germany.
FAU - Fulda, Simone
AU  - Fulda S
AD  - Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 
      Komturstr. 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), 
      Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. 
      Electronic address: simone.fulda@kgu.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150128
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (BCL2 protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (MCL1 protein, human)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Quinolines)
RN  - 0 (Reactive Oxygen Species)
RN  - 886U3H6UFF (Chloroquine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Chloroquine/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Enzyme Activation
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Lysosomes/drug effects/enzymology
MH  - Molecular Targeted Therapy
MH  - Mutation
MH  - Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - Quinolines/pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Rhabdomyosarcoma, Embryonal/*enzymology/genetics/*pathology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Transfection
OTO - NOTNLM
OT  - Apoptosis
OT  - Chloroquine
OT  - NVP-BEZ235
OT  - Rhabdomyosarcoma
EDAT- 2015/02/01 06:00
MHDA- 2015/07/15 06:00
CRDT- 2015/02/01 06:00
PHST- 2014/11/05 00:00 [received]
PHST- 2014/12/05 00:00 [revised]
PHST- 2014/12/05 00:00 [accepted]
PHST- 2015/02/01 06:00 [entrez]
PHST- 2015/02/01 06:00 [pubmed]
PHST- 2015/07/15 06:00 [medline]
AID - S0304-3835(14)00759-9 [pii]
AID - 10.1016/j.canlet.2014.12.016 [doi]
PST - ppublish
SO  - Cancer Lett. 2015 Apr 28;360(1):1-9. doi: 10.1016/j.canlet.2014.12.016. Epub 2015 
      Jan 28.