PMID- 36232303
OWN - NLM
STAT- MEDLINE
DCOM- 20221017
LR  - 20221207
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 19
DP  - 2022 Sep 20
TI  - Allyl-, Butyl- and Phenylethyl-Isothiocyanate Modulate Akt-mTOR and Cyclin-CDK 
      Signaling in Gemcitabine- and Cisplatin-Resistant Bladder Cancer Cell Lines.
LID - 10.3390/ijms231910996 [doi]
LID - 10996
AB  - Combined cisplatin-gemcitabine treatment causes rapid resistance development in 
      patients with advanced urothelial carcinoma. The present study investigated the 
      potential of the natural isothiocyanates (ITCs) allyl-isothiocyanate (AITC), 
      butyl-isothiocyanate (BITC), and phenylethyl-isothiocyanate (PEITC) to suppress 
      growth and proliferation of gemcitabine- and cisplatin-resistant bladder cancer 
      cells lines. Sensitive and gemcitabine- and cisplatin-resistant RT112, T24, and 
      TCCSUP cells were treated with the ITCs, and tumor cell growth, proliferation, 
      and clone formation were evaluated. Apoptosis induction and cell cycle 
      progression were investigated as well. The molecular mode of action was 
      investigated by evaluating cell cycle-regulating proteins (cyclin-dependent 
      kinases (CDKs) and cyclins A and B) and the mechanistic target of the rapamycin 
      (mTOR)-AKT signaling pathway. The ITCs significantly inhibited growth, 
      proliferation and clone formation of all tumor cell lines (sensitive and 
      resistant). Cells were arrested in the G2/M phase, independent of the type of 
      resistance. Alterations of both the CDK-cyclin axis and the Akt-mTOR signaling 
      pathway were observed in AITC-treated T24 cells with minor effects on apoptosis 
      induction. In contrast, AITC de-activated Akt-mTOR signaling and induced 
      apoptosis in RT112 cells, with only minor effects on CDK expression. It is 
      concluded that AITC, BITC, and PEITC exert tumor-suppressive properties on 
      cisplatin- and gemcitabine-resistant bladder cancer cells, whereby the molecular 
      action may differ among the cell lines. The integration of these ITCs into the 
      gemcitabine-/cisplatin-based treatment regimen might optimize bladder cancer 
      therapy.
FAU - Rutz, Jochen
AU  - Rutz J
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Maxeiner, Sebastian
AU  - Maxeiner S
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Grein, Timothy
AU  - Grein T
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Sonnenburg, Marlon
AU  - Sonnenburg M
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Khadir, Salma El
AU  - Khadir SE
AD  - Department of Urology, Goethe-University, 60590 Frankfurt am Main, Germany.
FAU - Makhatelashvili, Nino
AU  - Makhatelashvili N
AD  - Department of Urology, Goethe-University, 60590 Frankfurt am Main, Germany.
FAU - Mann, Johanna
AU  - Mann J
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Xie, Hui
AU  - Xie H
AUID- ORCID: 0000-0002-6219-1696
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Cinatl, Jindrich
AU  - Cinatl J
AD  - Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, 
      Germany.
FAU - Thomas, Anita
AU  - Thomas A
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Chun, Felix K-H
AU  - Chun FK
AD  - Department of Urology, Goethe-University, 60590 Frankfurt am Main, Germany.
FAU - Haferkamp, Axel
AU  - Haferkamp A
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Blaheta, Roman A
AU  - Blaheta RA
AUID- ORCID: 0000-0002-0129-7972
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
FAU - Tsaur, Igor
AU  - Tsaur I
AUID- ORCID: 0000-0001-5107-3523
AD  - Department of Urology and Pediatric Urology, University Medical Center Mainz, 
      55131 Mainz, Germany.
LA  - eng
GR  - N/A/Brigitta & Norbert Muth Stiftung, Wiesbaden, Germany/
GR  - N/A/Repha GmbH, Langenhagen, Germany/
PT  - Journal Article
DEP - 20220920
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cyclins)
RN  - 0 (Isothiocyanates)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 3129-90-6 (isothiocyanic acid)
RN  - 4Y31800S6C (butyl isothiocyanate)
RN  - 62414-75-9 (2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate)
RN  - 6U7TFK75KV (phenethyl isothiocyanate)
RN  - BN34FX42G3 (allyl isothiocyanate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - Q20Q21Q62J (Cisplatin)
RN  - W36ZG6FT64 (Sirolimus)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Apoptosis
MH  - *Carcinoma, Transitional Cell
MH  - Cell Line, Tumor
MH  - Cisplatin/pharmacology
MH  - Cyclin-Dependent Kinases/metabolism
MH  - Cyclins/metabolism
MH  - Deoxycytidine/analogs & derivatives
MH  - Humans
MH  - Isothiocyanates/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Urinary Bladder Neoplasms/metabolism
MH  - Gemcitabine
PMC - PMC9570347
OTO - NOTNLM
OT  - Akt-mTOR signaling
OT  - CDK-cyclin axis
OT  - bladder cancer
OT  - drug resistance
OT  - isothiocyanates
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript; or in the decision to publish the results.
EDAT- 2022/10/15 06:00
MHDA- 2022/10/18 06:00
PMCR- 2022/09/20
CRDT- 2022/10/14 02:06
PHST- 2022/08/19 00:00 [received]
PHST- 2022/09/12 00:00 [revised]
PHST- 2022/09/14 00:00 [accepted]
PHST- 2022/10/14 02:06 [entrez]
PHST- 2022/10/15 06:00 [pubmed]
PHST- 2022/10/18 06:00 [medline]
PHST- 2022/09/20 00:00 [pmc-release]
AID - ijms231910996 [pii]
AID - ijms-23-10996 [pii]
AID - 10.3390/ijms231910996 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Sep 20;23(19):10996. doi: 10.3390/ijms231910996.