title: Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma.
abstract: The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression.
authors.affiliation: Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan.
authors.forename: Makio
authors.initials: M
authors.lastname: Moriya
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishikawa
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Mir Alireza
authors.initials: MA
authors.lastname: Hoda
authors.affiliation: Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Oda
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.affiliation: Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Watanabe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D000068437:Pemetrexed; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D010982:Platelet-Derived Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D000068437:Pemetrexed; D006147:Guanine; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus