Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: Synergism with chemotherapy

Mir Alireza Hoda, Amir Mohamed, Bahil Ghanim, Martin Filipits, B. Hegedűs, Masaya Tamura, Judit Berta, Bernd Kubista, B. Döme, Michael Grusch, Ulrike Setinek, Michael Micksche, Walter Klepetko, Walter Berger

Research output: Contribution to journalArticle

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Abstract

Introduction: Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy. Methods: Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin. Results: Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin. Conclusion: The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.

Original languageEnglish
Pages (from-to)852-863
Number of pages12
JournalJournal of Thoracic Oncology
Volume6
Issue number5
DOIs
Publication statusPublished - May 2011

Fingerprint

Sirolimus
Drug Therapy
Mesothelioma
Growth
Cisplatin
Cell Line
Severe Combined Immunodeficiency
Heterografts
Phosphorylation
Malignant Mesothelioma
temsirolimus
In Vitro Techniques
S 6
Asbestos
Cytostatic Agents
Hypersensitivity
Radiotherapy
Immunohistochemistry
Apoptosis

Keywords

  • Chemotherapy
  • Cisplatin resistance
  • Mesothelioma
  • mTOR
  • Temsirolimus

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo : Synergism with chemotherapy. / Hoda, Mir Alireza; Mohamed, Amir; Ghanim, Bahil; Filipits, Martin; Hegedűs, B.; Tamura, Masaya; Berta, Judit; Kubista, Bernd; Döme, B.; Grusch, Michael; Setinek, Ulrike; Micksche, Michael; Klepetko, Walter; Berger, Walter.

In: Journal of Thoracic Oncology, Vol. 6, No. 5, 05.2011, p. 852-863.

Research output: Contribution to journalArticle

Hoda, MA, Mohamed, A, Ghanim, B, Filipits, M, Hegedűs, B, Tamura, M, Berta, J, Kubista, B, Döme, B, Grusch, M, Setinek, U, Micksche, M, Klepetko, W & Berger, W 2011, 'Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: Synergism with chemotherapy', Journal of Thoracic Oncology, vol. 6, no. 5, pp. 852-863. https://doi.org/10.1097/JTO.0b013e31820e1a25
Hoda, Mir Alireza ; Mohamed, Amir ; Ghanim, Bahil ; Filipits, Martin ; Hegedűs, B. ; Tamura, Masaya ; Berta, Judit ; Kubista, Bernd ; Döme, B. ; Grusch, Michael ; Setinek, Ulrike ; Micksche, Michael ; Klepetko, Walter ; Berger, Walter. / Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo : Synergism with chemotherapy. In: Journal of Thoracic Oncology. 2011 ; Vol. 6, No. 5. pp. 852-863.
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AU - Hoda, Mir Alireza

AU - Mohamed, Amir

AU - Ghanim, Bahil

AU - Filipits, Martin

AU - Hegedűs, B.

AU - Tamura, Masaya

AU - Berta, Judit

AU - Kubista, Bernd

AU - Döme, B.

AU - Grusch, Michael

AU - Setinek, Ulrike

AU - Micksche, Michael

AU - Klepetko, Walter

AU - Berger, Walter

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