PMID- 26405178
OWN - NLM
STAT- MEDLINE
DCOM- 20160212
LR  - 20220129
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 88
IP  - 6
DP  - 2015 Dec
TI  - A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and 
      Autophagy and Alleviates Mutant A53T alpha-Synuclein Toxicity.
PG  - 1045-54
LID - 10.1124/mol.115.101451 [doi]
AB  - A potential cause of neurodegenerative diseases, including Parkinson's disease 
      (PD), is protein misfolding and aggregation that in turn leads to neurotoxicity. 
      Targeting Hsp90 is an attractive strategy to halt neurodegenerative diseases, and 
      benzoquinone ansamycin (BQA) Hsp90 inhibitors such as geldanamycin (GA) and 
      17-(allylamino)-17-demethoxygeldanamycin have been shown to be beneficial in 
      mutant A53T alpha-synuclein PD models. However, current BQA inhibitors result in 
      off-target toxicities via redox cycling and/or arylation of nucleophiles at the 
      C19 position. We developed novel 19-substituted BQA (19BQA) as a means to prevent 
      arylation. In this study, our data demonstrated that 19-phenyl-GA, a lead 19BQA 
      in the GA series, was redox stable and exhibited little toxicity relative to its 
      parent quinone GA in human dopaminergic SH-SY5Y cells as examined by oxygen 
      consumption, trypan blue, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium 
      bromide (MTT), and apoptosis assays. Meanwhile, 19-phenyl-GA retained the ability 
      to induce autophagy and potentially protective heat shock proteins (HSPs) such as 
      Hsp70 and Hsp27. We found that transduction of A53T, but not wild type (WT) 
      alpha-synuclein, induced toxicity in SH-SY5Y cells. 19-Phenyl-GA decreased oligomer 
      formation and toxicity of A53T alpha-synuclein in transduced cells. Mechanistic 
      studies indicated that mammalian target of rapamycin (mTOR)/p70 ribosomal S6 
      kinase signaling was activated by A53T but not WT alpha-synuclein, and 19-phenyl-GA 
      decreased mTOR activation that may be associated with A53T alpha-synuclein toxicity. 
      In summary, our results indicate that 19BQAs such as 19-phenyl-GA may provide a 
      means to modulate protein-handling systems including HSPs and autophagy, thereby 
      reducing the aggregation and toxicity of proteins such as mutant A53T 
      alpha-synuclein.
CI  - Copyright (c) 2015 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Xiong, Rui
AU  - Xiong R
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Zhou, Wenbo
AU  - Zhou W
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Siegel, David
AU  - Siegel D
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Kitson, Russell R A
AU  - Kitson RR
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Freed, Curt R
AU  - Freed CR
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Moody, Christopher J
AU  - Moody CJ
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.).
FAU - Ross, David
AU  - Ross D
AD  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and 
      Pharmaceutical Sciences (R.X., D.S., D.R.), and Department of Medicine, Division 
      of Clinical Pharmacology and Toxicology (W.Z., C.R.F.), University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado; and School of Chemistry, University of 
      Nottingham, Nottingham, United Kingdom (R.R.A.K., C.J.M.) 
      David.Ross@ucdenver.edu.
LA  - eng
GR  - R01ES018943/ES/NIEHS NIH HHS/United States
GR  - G-1002/PUK_/Parkinson's UK/United Kingdom
GR  - R01 ES018943/ES/NIEHS NIH HHS/United States
GR  - CA51210/CA/NCI NIH HHS/United States
GR  - R01 CA051210/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150924
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Benzoquinones)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (alpha-Synuclein)
RN  - 3T006GV98U (quinone)
SB  - IM
MH  - Autophagy/*drug effects/physiology
MH  - Benzoquinones/chemistry/*pharmacology
MH  - Cell Line, Tumor
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Mutation/*physiology
MH  - alpha-Synuclein/*genetics/*toxicity
PMC - PMC4658594
EDAT- 2015/09/26 06:00
MHDA- 2016/02/13 06:00
PMCR- 2016/12/01
CRDT- 2015/09/26 06:00
PHST- 2015/08/20 00:00 [received]
PHST- 2015/09/16 00:00 [accepted]
PHST- 2015/09/26 06:00 [entrez]
PHST- 2015/09/26 06:00 [pubmed]
PHST- 2016/02/13 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - mol.115.101451 [pii]
AID - MOL_101451 [pii]
AID - 10.1124/mol.115.101451 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2015 Dec;88(6):1045-54. doi: 10.1124/mol.115.101451. Epub 2015 Sep 
      24.