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ID 51441
FullText URL
Author
Nishikawa, Toshio
Takaoka, Munenori
Ohara, Toshiaki
Tomono, Yasuko
Hao, Huifang
Bao, Xiaohong
Fukazawa, Takuya
Wang, Zhigang
Sakurama, Kazufumi
Fujiwara, Yasuhiro
Yamatsuji, Tomoki
Tanaka, Noriaki
Naomoto, Yoshio
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 alpha (HIF-1 alpha), 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.
Keywords
temsirolimus
esophageal cancer
mTOR
prolonged survival
molecular-targeted therapy
Published Date
2013-03
Publication Title
Cancer Biology & Therapy
Volume
volume14
Issue
issue3
Publisher
Landes Bioscience
Start Page
230
End Page
236
ISSN
1538-4047
Content Type
Journal Article
Official Url
http://dx.doi.org/10.4161/cbt.23294
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/51446
language
英語
File Version
author
Refereed
True
DOI
Web of Sience KeyUT