PMID- 29299126
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220314
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 66
DP  - 2017 Dec 15
TI  - HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder 
      cancer cells.
PG  - 110016-110028
LID - 10.18632/oncotarget.22454 [doi]
AB  - INTRODUCTION: Although the mechanistic target of rapamycin (mTOR) might be a 
      promising molecular target to treat advanced bladder cancer, resistance develops 
      under chronic exposure to an mTOR inhibitor (everolimus, temsirolimus). Based on 
      earlier studies, we proposed that histone deacetylase (HDAC) blockade might 
      circumvent resistance and investigated whether HDAC inhibition has an impact on 
      growth of bladder cancer cells with acquired resistance towards temsirolimus. 
      RESULTS: The HDAC inhibitor valproic acid (VPA) significantly inhibited growth, 
      proliferation and caused G0/G1 phase arrest in RT112(res) and UMUC-3(res). cdk1, 
      cyclin B, cdk2, cyclin A and Skp1 p19 were down-regulated, p27 was elevated. 
      Akt-mTOR signaling was deactivated, whereas acetylation of histone H3 and H4 in 
      RT112(res) and UMUC-3(res) increased in the presence of VPA. Knocking down cdk2 
      or cyclin A resulted in a significant growth blockade of RT112(res) and 
      UMUC-3(res). MATERIALS AND METHODS: Parental (par) and resistant (res) RT112 and 
      UMUC-3 cells were exposed to the HDAC inhibitor VPA. Tumor cell growth, 
      proliferation, cell cycling and expression of cell cycle regulating proteins were 
      then evaluated. siRNA blockade was used to investigate the functional impact of 
      the proteins. CONCLUSIONS: HDAC inhibition induced a strong response of 
      temsirolimus-resistant bladder cancer cells. Therefore, the 
      temsirolimus-VPA-combination might be an innovative strategy for bladder cancer 
      treatment.
FAU - Juengel, Eva
AU  - Juengel E
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
AD  - Current address: Department of Urology and Pediatric Urology, Mainz University 
      Medical Center, Mainz, Germany.
FAU - Najafi, Ramin
AU  - Najafi R
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
FAU - Rutz, Jochen
AU  - Rutz J
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
FAU - Maxeiner, Sebastian
AU  - Maxeiner S
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
FAU - Makarevic, Jasmina
AU  - Makarevic J
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
FAU - Roos, Frederik
AU  - Roos F
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
AD  - Current address: Department of Urology and Pediatric Urology, Mainz University 
      Medical Center, Mainz, Germany.
FAU - Tsaur, Igor
AU  - Tsaur I
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
AD  - Current address: Department of Urology and Pediatric Urology, Mainz University 
      Medical Center, Mainz, Germany.
FAU - Haferkamp, Axel
AU  - Haferkamp A
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
AD  - Current address: Department of Urology and Pediatric Urology, Mainz University 
      Medical Center, Mainz, Germany.
FAU - Blaheta, Roman A
AU  - Blaheta RA
AD  - Department of Urology, Goethe-University, Frankfurt am Main, Germany.
LA  - eng
PT  - Journal Article
DEP - 20171106
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5746361
OTO - NOTNLM
OT  - HDAC inhibition
OT  - bladder cancer
OT  - temsirolimus-resistance
OT  - tumor growth
OT  - valproic acid (VPA)
COIS- CONFLICTS OF INTEREST None.
EDAT- 2018/01/05 06:00
MHDA- 2018/01/05 06:01
PMCR- 2017/12/15
CRDT- 2018/01/05 06:00
PHST- 2017/06/01 00:00 [received]
PHST- 2017/10/12 00:00 [accepted]
PHST- 2018/01/05 06:00 [entrez]
PHST- 2018/01/05 06:00 [pubmed]
PHST- 2018/01/05 06:01 [medline]
PHST- 2017/12/15 00:00 [pmc-release]
AID - 22454 [pii]
AID - 10.18632/oncotarget.22454 [doi]
PST - epublish
SO  - Oncotarget. 2017 Nov 6;8(66):110016-110028. doi: 10.18632/oncotarget.22454. 
      eCollection 2017 Dec 15.