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

Title
Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells
Authors
Kim, HyeraLee, Su JinLee, In KyoungMin, Suejean C.Sung, Hyun HwanJeong, Byong ChangLee, JeeyunPark, Se Hoon
Ewha Authors
이수진
SCOPUS Author ID
이수진scopus
Issue Date
2020
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
1422-0067JCR Link
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol. 21, no. 8
Keywords
bladder cancerAKTmTORAZD5363AZD2014BEZ235
Publisher
MDPI
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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 mu M 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.
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DOI
10.3390/ijms21082825
Appears in Collections:
의과대학 > 의학과 > Journal papers
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