PMID- 32325639
OWN - NLM
STAT- MEDLINE
DCOM- 20210202
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 8
DP  - 2020 Apr 18
TI  - Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on 
      Bladder Cancer Cells.
LID - 10.3390/ijms21082825 [doi]
LID - 2825
AB  - Despite comprehensive genomic analyses, no targeted therapies are approved for 
      bladder cancer. Here, we investigate whether a single and combination therapy 
      with targeted agents exert antitumor effects on bladder cancer cells through 
      genomic alterations using a three-dimensional (3D) high-throughput screening 
      (HTS) platform. Seven human bladder cancer cell lines were used to screen 24 
      targeted agents. The effects of 24 targeted agents were dramatically different 
      according to the genomic alterations of bladder cancer cells. BEZ235 (dual 
      phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) 
      inhibitor) showed antitumor effects against most cell lines, while AZD2014 (mTOR 
      inhibitor) had an IC50 value lower than 2 muM in 5637, J82, and RT4 cell lines. 
      AZD5363 (protein kinase B (AKT) inhibitor) exerted antitumor effects on 5637, 
      J82, and 253J-BV cells. J82 cells (PI3KCA and mTOR mutations) were sensitive to 
      AZD5363, AZD2014, and BEZ235 alone or in AZD5363/AZD2014 and AZD5363/BEZ235 
      combinations. Although all single drugs suppressed cell proliferation, the 
      combination of drugs exhibited synergistic effects on cell viability and colony 
      formation. The synergistic effects of the combination therapy on the 
      PI3K/Akt/mTOR pathway, apoptosis, and EMT were evident in Western blotting. Thus, 
      the 3D culture-based HTS platform could serve as a useful preclinical tool to 
      evaluate various drug combinations.
FAU - Kim, Hyera
AU  - Kim H
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
AD  - Division of Hematology-Oncology, Department of Internal Medicine, Keimyung 
      University Dongsan Hospital, Daegu 42601, Korea.
FAU - Lee, Su Jin
AU  - Lee SJ
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
AD  - Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans 
      University College of Medicine, Seoul 07804, Korea.
FAU - Lee, In Kyoung
AU  - Lee IK
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
FAU - Min, Suejean C
AU  - Min SC
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
FAU - Sung, Hyun Hwan
AU  - Sung HH
AD  - Department of Urology, Samsung Medical Center, Sungkyunkwan University School of 
      Medicine, Seoul 06351, Korea.
FAU - Jeong, Byong Chang
AU  - Jeong BC
AD  - Department of Urology, Samsung Medical Center, Sungkyunkwan University School of 
      Medicine, Seoul 06351, Korea.
FAU - Lee, Jeeyun
AU  - Lee J
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
FAU - Park, Se Hoon
AU  - Park SH
AD  - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
      Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
LA  - eng
GR  - HI14C2750, HI14C3418/Korea Health Industry Development Institute/Republic of 
      Korea
PT  - Journal Article
DEP - 20200418
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Imidazoles)
RN  - 0 (Morpholines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (Quinolines)
RN  - 0BSC3P4H5X (vistusertib)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - WFR23M21IE (capivasertib)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Benzamides/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Drug Synergism
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Inhibitory Concentration 50
MH  - Morpholines/pharmacology
MH  - Mutation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism
MH  - Pyrimidines/pharmacology
MH  - Pyrroles/pharmacology
MH  - Quinolines/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Urinary Bladder Neoplasms/*drug therapy/enzymology/genetics/metabolism
PMC - PMC7215775
OTO - NOTNLM
OT  - AKT
OT  - AZD2014
OT  - AZD5363
OT  - BEZ235
OT  - bladder cancer
OT  - mTOR
COIS- The authors declare no conflict of interest.
EDAT- 2020/04/25 06:00
MHDA- 2021/02/03 06:00
PMCR- 2020/04/01
CRDT- 2020/04/25 06:00
PHST- 2020/03/16 00:00 [received]
PHST- 2020/04/12 00:00 [revised]
PHST- 2020/04/16 00:00 [accepted]
PHST- 2020/04/25 06:00 [entrez]
PHST- 2020/04/25 06:00 [pubmed]
PHST- 2021/02/03 06:00 [medline]
PHST- 2020/04/01 00:00 [pmc-release]
AID - ijms21082825 [pii]
AID - ijms-21-02825 [pii]
AID - 10.3390/ijms21082825 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Apr 18;21(8):2825. doi: 10.3390/ijms21082825.