Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells

Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC50 of <1nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1h, accompanied by an increased cell population in the G0/G1 phase, but according to flow cytometry, the cell population did not increase in the sub-G0 phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus=1239 vs 698cm3; P<0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus=53.5 vs 72.5days; P<0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.

Original languageEnglish
Pages (from-to)1344-1349
Number of pages6
JournalCancer Science
Volume102
Issue number7
DOIs
Publication statusPublished - Jul 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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