title: Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice.
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.
authors.affiliation: Department of Gastroenterological Surgery and Surgical Oncology, Graduate School of Medicine Dentistry, Okayama University, Okayama, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohara
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Huifang
authors.initials: H
authors.lastname: Hao
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Bao
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Sakurama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Motoki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: esophageal cancer; mTOR; molecular-targeted therapy; prolonged survival; temsirolimus