Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice

Toshio Nishikawa, Munenori Takaoka, Toshiaki Ohara, Yasuko Tomono, Huifang Hao, Xiaohong Bao, Takuya Fukazawa, Zhigang Wang, Kazufumi Sakurama, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

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Abstract

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Original languageEnglish
Pages (from-to)230-236
Number of pages7
JournalCancer Biology and Therapy
Volume14
Issue number3
DOIs
Publication statusPublished - Mar 1 2013

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Keywords

  • Esophageal cancer
  • MTOR
  • Molecular-targeted therapy
  • Prolonged survival
  • Temsirolimus

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Nishikawa, T., Takaoka, M., Ohara, T., Tomono, Y., Hao, H., Bao, X., Fukazawa, T., Wang, Z., Sakurama, K., Fujiwara, Y., Motoki, T., Shirakawa, Y., Yamatsuji, T., Tanaka, N., Fujiwara, T., & Naomoto, Y. (2013). Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. Cancer Biology and Therapy, 14(3), 230-236. https://doi.org/10.4161/cbt.23294