COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines

Our plain-English summary of COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines, by S.L. O'Kane, G.L. Eagle, J. Greenman, et al (Lung Cancer, 2010).

The study

• Authors: S.L. O'Kane, G.L. Eagle, J. Greenman, M.J. Lind, L. Cawkwell
• Journal: Lung Cancer
• Published: 2010;67(2):160-5
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Although malignant pleural mesothelioma is a rare tumour, its incidence is increasing. The prognosis remains very poor with an average survival of 10 months from diagnosis. The choice of chemotherapy regimens for mesothelioma patients is limited and new approaches are required. COX-2 inhibition induces apoptosis in a variety of tumour cell lines. The cytotoxic effect of conventional drugs may be enhanced by the addition of a COX-2 inhibitor. In order to identify possible new therapeutic approaches we aimed to determine whether the addition of COX-2 inhibitors would enhance the cytotoxic effect of chemotherapeutic agents in mesothelioma cell lines.

Materials And Methods: Three mesothelioma cell lines MSTO-211H, NCI-H2052 and NCI-H2452 were utilised. Using the COX-2 positive A549 lung cancer cell line as control, all cell lines were assayed using an MTT assay with non-specific COX-2 inhibitors (sulindac and flurbiprofen), specific COX-2 inhibitors (DuP-697 and NS-398), and chemotherapeutic agents (cisplatin, vinorelbine and pemetrexed).

Results: All cell lines exhibited COX-2 expression by western blotting using two antibodies. The addition of either DuP-697 or NS-398 increased the sensitivity to pemetrexed in all cell lines.

Conclusion: These findings suggest that the design of novel pemetrexed-containing combination regimens with increased cytotoxicity may be feasible.

Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

In plain English

This was a laboratory study of cancer cells grown in dishes, not of patients, and it did not look at asbestos exposure. The authors, at the University of Hull in the UK, used three mesothelioma cell lines (MSTO-211H, NCI-H2052 and NCI-H2452) and, for comparison, the A549 lung cancer cell line. All four cell lines made the COX-2 enzyme. The authors measured how well three chemotherapy drugs (cisplatin, vinorelbine and pemetrexed) reduced cell growth, alone and when combined with one of two specific COX-2 blocking drugs, DuP-697 or NS-398. Adding either blocker made all cell lines more sensitive to pemetrexed. The dose needed to halve cell growth fell by more than 4-fold in NCI-H2052 cells and by up to 26.8-fold in MSTO-211H cells. Adding the blockers did not improve the effect of cisplatin or vinorelbine in any mesothelioma cell line. The authors concluded that new pemetrexed-containing combinations with greater cell-killing effect may be feasible. They noted that some COX-2 inhibitors carry significant cardiovascular risks and that how these drugs work still needs study.

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) experiment on cancer cell lines, measuring cell growth with an MTT assay
• Who was studied: No people were studied. The study used three mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H2452) obtained from the American Type Culture Collection, plus the A549 lung cancer cell line as a COX-2-positive control. The work was done at the University of Hull, UK.
• Exposure: No asbestos exposure was studied. The cells were treated with drugs: non-specific COX-2 inhibitors (sulindac, flurbiprofen), specific COX-2 inhibitors (DuP-697, NS-398) and chemotherapy drugs (cisplatin, vinorelbine, pemetrexed), alone and in combination.
• Main results:
  • All three mesothelioma cell lines showed COX-2 in all replicate samples, with both antibodies tested.
  • DuP-697 used alone reached a half-maximal inhibitory concentration (IC50) in NCI-H2052 (86), A549 (169) and MSTO-211H (231) cells, but not in NCI-H2452 cells. Units are printed as 'M'.
  • Adding DuP-697 or NS-398 to cisplatin or vinorelbine did not enhance cytotoxicity in any of the three mesothelioma cell lines.
  • IC50 values went up (the drug worked less well) when the inhibitors were added to cisplatin in NCI-H2452 cells and to vinorelbine in MSTO-211H cells.
  • In the A549 lung cancer cells, but not in the mesothelioma cells, adding a COX-2 inhibitor enhanced the effect of cisplatin: a 3.7-fold decrease in IC50 with DuP-697 and a 3.1-fold decrease with NS-398.
  • No additive effects were seen with vinorelbine plus either specific inhibitor in any cell line.
  • All cell lines became more sensitive to pemetrexed when either specific COX-2 inhibitor was added.
  • MSTO-211H cells: IC50 for pemetrexed fell 26.8-fold with NS-398 and 12-fold with DuP-697.
  • NCI-H2052 cells: IC50 for pemetrexed fell more than 4-fold with each inhibitor.
  • NCI-H2452 cells: IC50 for pemetrexed fell 6.5-fold with NS-398 and 7.4-fold with DuP-697.
  • A549 lung cancer cells: IC50 for pemetrexed fell 6.7-fold with NS-398 and 8.7-fold with DuP-697.
• The authors' conclusion: The authors concluded that their findings suggest it may be feasible to design new pemetrexed-containing combination regimens with increased cytotoxicity.
• Limitations the authors state:
  • Some COX-2 inhibitors are associated with significant cardiovascular risks, so the choice of drug for clinical trials matters.
  • The mechanism of action of the active agents is not established and needs further laboratory work.
  • Some COX-2 inhibitors may not act through COX-2 at all.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Mesothelioma, Pleural Mesothelioma, Prognosis, Chemotherapy, Apoptosis, Lung Cancer, Cisplatin.

Related studies

• Proteomic (antibody microarray) exploration of the molecular mechanism of action of the specific COX-2 inhibitor DuP 697 — V. Agarwal, V.C. Hodgkinson, et al. (2013)
• Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy — G. Toyokawa, M. Takenoyama, et al. (2014)
• Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction — K.E. Hwang, Y.S. Kim, et al. (2014)
• Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells — L. Su, G. Liu, et al. (2011)
• Successful salvage chemotherapy with gemcitabine and vinorelbine in a malignant pleural mesothelioma patient previously treated with pemetrexed — T. Agatsuma, T. Koizumi, et al. (2010)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)

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