Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma

Our plain-English summary of Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma, by M. Moriya, T. Yamada, M. Tamura, et al (Oncology Reports, 2014).

The study

• Authors: M. Moriya, T. Yamada, M. Tamura, D. Ishikawa, M.A. Hoda, I. Matsumoto, W. Klepetko, M. Oda, S. Yano, G. Watanabe
• Journal: Oncology Reports
• Published: 2014;31(3):1109-15
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study tested temsirolimus, a drug that blocks the cell-growth protein mTOR. It was tried on four malignant pleural mesothelioma cell lines (H226, H290, Y-meso14 and MSTO-211H) grown in dishes, alone and with the chemotherapy drug cisplatin. MSTO-211H, highly sensitive to pemetrexed alone, was excluded from tests of temsirolimus plus pemetrexed. The study did not examine asbestos exposure or treat patients. Temsirolimus reduced the viability and the numbers of cells in all four lines. The dose that halved viability ranged from about 0.2 to about 2 micromolar, depending on the line. Non-cancerous comparison cells were affected less. In all four lines, temsirolimus combined with cisplatin worked significantly better than either drug alone. The temsirolimus-pemetrexed combination worked better than each drug alone only in Y-meso14 cells. Temsirolimus strongly reduced the cells' release of VEGF and moderately reduced PDGF-AA, two proteins linked to tumor blood-vessel growth. In tumor samples from 5 patients, activated (phosphorylated) mTOR was seen in 2, and VEGF and PDGF-AA in 4. The authors concluded that temsirolimus may benefit a subset of patients with high mTOR expression.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cultured cell lines, plus immunohistochemical staining of tumor specimens from patients
• Who was studied: Four malignant pleural mesothelioma cell lines (H226, H290, Y-meso14, MSTO-211H), three non-cancerous cell lines (Met-5A mesothelial cells, MRC-5 and IMR-90 lung fibroblasts), and tumor specimens from 5 MPM patients at Kanazawa University Hospital, Japan
• Exposure: Drug treatment, not asbestos: temsirolimus (0 to 10 µM), cisplatin (0 to 10 µg/ml) and pemetrexed (0 to 10 µg/ml) for 72 hours, alone or in combination
• Main results:
  • In the MPM cell lines, the temsirolimus concentration that cut viability by half was about 2 µM (H226), 0.5 µM (H290), 0.5 µM (Y-meso14) and 0.2 µM (MSTO-211H)
  • Temsirolimus reduced cell numbers in all MPM cell lines tested
  • Temsirolimus inhibited the viability of the non-neoplastic cells less than that of the MPM cell lines
  • In all MPM cell lines, 0.01 µM temsirolimus plus 0.3 µg/ml cisplatin was significantly more effective than either drug alone
  • MSTO-211H was excluded from the temsirolimus-pemetrexed combination tests because it was highly sensitive to pemetrexed
  • Among the three lines tested, temsirolimus plus pemetrexed was more effective than each drug alone only in Y-meso14 cells
  • In all four MPM cell lines, temsirolimus strongly inhibited VEGF production and moderately inhibited PDGF-AA production
  • Cleaved caspase-3, a marker of cell death (apoptosis), increased with dose in H226 and Y-meso14 cells but not in MSTO-211H and H290 cells
  • In the 5 patient tumor specimens, mTOR was expressed in 3
  • In the 5 patient tumor specimens, phosphorylated mTOR was seen in 2
  • In the 5 patient tumor specimens, VEGF and PDGF-AA were expressed in 4
• The authors' conclusion: The authors concluded that temsirolimus inhibits MPM cell proliferation, strengthens the effect of platinum-based chemotherapy, and may be beneficial for a subset of MPM patients with high mTOR expression

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Carcinoma, Cisplatin, Pemetrexed (Alimta), Cytokine, Immunohistochemistry, Platelet-Derived Growth Factor (PDGF), Angiogenesis.

Related studies

• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM) — S.H. Ou, J. Moon, et al. (2015)
• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy — B.K. Bitanihirwe, M. Meerang, et al. (2014)
• Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy — M.A. Hoda, A. Mohamed, et al. (2011)
• Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo — S. Miyoshi, H. Hamada, et al. (2012)

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