PMID- 25308700
OWN - NLM
STAT- MEDLINE
DCOM- 20150102
LR  - 20141013
IS  - 1879-3592 (Electronic)
IS  - 1383-5718 (Linking)
VI  - 773
DP  - 2014 Oct
TI  - HSP90 inhibitor CH5164840 induces micronuclei in TK6 cells via an aneugenic 
      mechanism.
PG  - 9-13
LID - S1383-5718(14)00220-4 [pii]
LID - 10.1016/j.mrgentox.2014.08.002 [doi]
AB  - Heat-shock protein 90 (HSP90) is a promising druggable target for therapy of 
      conditions including cancer, renal disease, and chronic neurodegenerative 
      diseases. Despite the possible beneficial effects of HSP90 inhibitors, some of 
      these agents present a genotoxicity liability. We have examined the mode of 
      action of micronucleus formation in TK6 cells by a novel and highly specific 
      HSP90 inhibitor, CH5164840, by means of an in vitro micronucleus test with 
      fluorescence in situ hybridization (FISH), gammaH2AX staining to detect DNA damage, 
      and microscopic observation of chromosomal alignment in mitotic cells. The 
      percentage of centromere-positive micronuclei induced by CH5164840 (FISH 
      analysis) was significant, but the percentage of centromere-negative ones was 
      not, suggesting that induction of micronuclei was due to a mechanism of 
      aneugenicity rather than DNA reactivity. This conclusion was further supported by 
      the result of co-staining gammaH2AX and the apoptosis marker caspase-3; the 
      predominant elevation of apoptotic gammaH2AX rather than non-apoptotic gammaH2AX 
      indicated little involvement of DNA-reactivity mechanisms. Microscopic 
      observation revealed asymmetric spindle microtubules and chromosomal misalignment 
      of metaphase cells. These data indicated that CH5164840 causes spindle 
      dysfunction that induces micronuclei. The risk/benefit ratio must be considered 
      in the development of HSP90 inhibitors.
CI  - Copyright (c) 2014 Elsevier B.V. All rights reserved.
FAU - Matsuzaki, Kaori
AU  - Matsuzaki K
AD  - Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, 
      Japan.
FAU - Harada, Asako
AU  - Harada A
AD  - Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, 
      Japan.
FAU - Tanaka, Kenji
AU  - Tanaka K
AD  - Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, 
      Japan.
FAU - Takeiri, Akira
AU  - Takeiri A
AD  - Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, 
      Japan.
FAU - Mishima, Masayuki
AU  - Mishima M
AD  - Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, 
      Japan. Electronic address: mishimamsy@chugai-pharm.co.jp.
LA  - eng
PT  - Journal Article
DEP - 20140820
PL  - Netherlands
TA  - Mutat Res Genet Toxicol Environ Mutagen
JT  - Mutation research. Genetic toxicology and environmental mutagenesis
JID - 101632149
RN  - 0 (Aneugens)
RN  - 0 (Benzoquinones)
RN  - 0 (CH5164840)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Lactams, Macrocyclic)
SB  - IM
MH  - Aneugens/*pharmacology
MH  - Benzoquinones/*pharmacology
MH  - Cells, Cultured
MH  - DNA Damage
MH  - Dose-Response Relationship, Drug
MH  - HSP90 Heat-Shock Proteins/antagonists & inhibitors
MH  - Humans
MH  - Lactams, Macrocyclic/*pharmacology
MH  - Lymphocytes/*drug effects/metabolism
MH  - Micronuclei, Chromosome-Defective/*chemically induced
MH  - Micronucleus Tests
MH  - Signal Transduction/drug effects/genetics
OTO - NOTNLM
OT  - Aneugen
OT  - FISH
OT  - HSP90
OT  - gammaH2AX
EDAT- 2014/10/14 06:00
MHDA- 2015/01/03 06:00
CRDT- 2014/10/14 06:00
PHST- 2014/07/04 00:00 [received]
PHST- 2014/08/08 00:00 [revised]
PHST- 2014/08/12 00:00 [accepted]
PHST- 2014/10/14 06:00 [entrez]
PHST- 2014/10/14 06:00 [pubmed]
PHST- 2015/01/03 06:00 [medline]
AID - S1383-5718(14)00220-4 [pii]
AID - 10.1016/j.mrgentox.2014.08.002 [doi]
PST - ppublish
SO  - Mutat Res Genet Toxicol Environ Mutagen. 2014 Oct;773:9-13. doi: 
      10.1016/j.mrgentox.2014.08.002. Epub 2014 Aug 20.