Synergistic effects of combination therapy with akt and mtor inhibitors on bladder cancer cells

Hyera Kim, Su Jin Lee, In Kyoung Lee, Suejean C. Min, Hyun Hwan Sung, Byong Chang Jeong, Jeeyun Lee, Se Hoon Park

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article number2825
JournalInternational Journal of Molecular Sciences
Volume21
Issue number8
DOIs
StatePublished - 2 Apr 2020

Bibliographical note

Funding Information:
Funding: This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C2750, HI14C3418).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • AKT
  • AZD2014
  • AZD5363
  • BEZ235
  • Bladder cancer
  • MTOR

Fingerprint

Dive into the research topics of 'Synergistic effects of combination therapy with akt and mtor inhibitors on bladder cancer cells'. Together they form a unique fingerprint.

Cite this