Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells
- 주제(키워드) bladder cancer , AKT , mTOR , AZD5363 , AZD2014 , BEZ235
- 주제(기타) Biochemistry & Molecular Biology
- 주제(기타) Chemistry, Multidisciplinary
- 설명문(일반) [Kim, Hyera; Lee, Su Jin; Lee, In Kyoung; Min, Suejean C.; Lee, Jeeyun; Park, Se Hoon] Sungkyunkwan Univ, Sch Med, Div Hematol Oncol, Dept Med,Samsung Med Ctr, Seoul 06351, South Korea; [Kim, Hyera] Keimyung Univ, Dongsan Hosp, Div Hematol Oncol, Dept Internal Med, Daegu 42601, South Korea; [Lee, Su Jin] Ewha Womans Univ, Coll Med, Div Hematol Oncol, Dept Internal Med, Seoul 07804, South Korea; [Sung, Hyun Hwan; Jeong, Byong Chang] Sungkyunkwan Univ, Sch Med, Dept Urol, Samsung Med Ctr, Seoul 06351, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published
- 발행기관 MDPI
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000169420
- 본문언어 영어
- Published As https://dx.doi.org/10.3390/ijms21082825
- PubMed https://pubmed.ncbi.nlm.nih.gov/32325639
초록/요약
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.
more