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Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells

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Author(s)
Hyera KimSu Jin LeeIn Kyoung LeeSuejean C. MinHyun Hwan SungByong Chang JeongJeeyun LeeSe Hoon Park
Keimyung Author(s)
Kim, Hye Ra
Department
Dept. of Internal Medicine (내과학)
Journal Title
International Journal of Molecular Sciences
Issued Date
2020
Volume
21
Issue
8
Keyword
: bladder cancerAKTmTORAZD5363AZD2014BEZ235
Abstract
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 μM 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.
Keimyung Author(s)(Kor)
김혜라
Publisher
School of Medicine (의과대학)
Citation
Hyera Kim et al. (2020). Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells. International Journal of Molecular Sciences, 21(8), 2825. doi: 10.3390/ijms21082825
Type
Article
ISSN
1422-0067
Source
https://www.mdpi.com/1422-0067/21/8/2825
DOI
10.3390/ijms21082825
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43118
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
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