Cilengitide inhibits attachment and invasion of malignant pleural mesothelioma cells through antagonism of integrins αvβ3 and αvβ5

Our plain-English summary of Cilengitide inhibits attachment and invasion of malignant pleural mesothelioma cells through antagonism of integrins αvβ3 and αvβ5, by N.C. Cheng, N. van Zandwijk, G. Reid (PloS One, 2014).

The study

• Authors: N.C. Cheng, N. van Zandwijk, G. Reid
• Journal: PloS One
• Published: 2014;9(3):e90374
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an almost invariably fatal, asbestos-related malignancy arising from the mesothelial membrane lining the thoracic cavities. Despite some improvements in treatment, therapy is not considered curative and median survival following diagnosis is less than 1 year. Although still classed as a rare cancer, the incidence of MPM is increasing, and the limited progress in treating the disease makes the identification of new therapies a priority. As there is evidence for expression of the integrins αvβ3 and αvβ5 in MPM, there is a rationale for investigating the effects on MPM of cilengitide, a synthetic peptide inhibitor of integrin αv heterodimer with high specificity for αvβ3 and αvβ5. In mesothelial cells (MC) and 7 MPM cell lines, growth inhibition by cilengitide was associated with the expression level of its target integrins. Furthermore, cilengitide caused cell detachment and subsequent death of anoikis-sensitive cells. It also suppressed invasion of MPM cells in monolayer and three-dimensional cultures. Gene knockdown experiments indicated that these effects of cilengitide were, at least partly, due to antagonism of αvβ3 and αvβ5.

In plain English

This was a laboratory study of cells grown in dishes. It did not study people or asbestos exposure. The authors tested cilengitide, a drug that blocks the integrins αvβ3 and αvβ5, on seven malignant pleural mesothelioma (MPM) cell lines and one non-malignant mesothelial cell line. Cilengitide made cells round up and detach. H28 and MM05, the lines with the most target integrin, were the most sensitive to growth inhibition, while MSTO-211H and REN were quite resistant. The drug did not kill all cells even at the highest dose. Growth was inhibited mainly in cells prone to dying once detached (anoikis), and most cells grown on collagen-coated plates became completely resistant. In three-day tests, adding sub-toxic doses of cilengitide had no significant effect on how toxic cisplatin, gemcitabine or pemetrexed were to the cells. Cilengitide strongly suppressed invasion only in H28, the one line with strong αvβ3. Reducing the β3 or β5 integrin genes' activity with siRNA partly reproduced the detachment and invasion effects, but did not affect cell growth at the low dose used. The authors concluded that integrins should be considered potential treatment targets for MPM.

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 cultured cell lines, comparing drug treatment with gene knockdown
• Who was studied: Seven malignant pleural mesothelioma cell lines (H28, H226, H2052, H2452, MSTO-211H, MM05, REN) and the non-malignant mesothelial cell line MeT-5A, studied at the Asbestos Diseases Research Institute, University of Sydney, Australia. In an additional analysis whose results were not shown, the authors also tested six primary mesothelioma cultures.
• Exposure: Cilengitide, a synthetic peptide that inhibits αv integrins with high specificity for αvβ3 and αvβ5, given at a range of concentrations. The authors also used siRNA knockdown of the integrin genes ITGB3 and ITGB5. Asbestos exposure was not studied.
• Main results:
  • Strong αvβ3 expression was found only in the H28 cell line. It was barely detected in the other cell lines.
  • Cilengitide affected the adhesion and shape of all the MPM cell lines tested. In some lines, such as H226 and MSTO-211H, most cells rounded up and detached within 24 hours.
  • H28 and MM05, the two cell lines with the highest expression of the drug's target integrins, were the most sensitive to growth inhibition by cilengitide. MSTO-211H and REN were quite resistant.
  • Cilengitide did not kill all cells even at the highest concentration tested (200 micromolar). The authors suggested it slows cell growth rather than killing cells outright.
  • The cell lines most resistant to death after detachment (anoikis), MSTO-211H and REN, were also the most resistant to cilengitide.
  • The mesothelial cells and most MPM cells grown on plates coated with collagen or basal membrane extract became completely resistant to cilengitide. H28 cells became only partially resistant.
  • In three-day growth inhibition assays, sub-toxic doses of cilengitide combined with cisplatin, gemcitabine or pemetrexed had no significant effect on the toxicity of these chemotherapy drugs.
  • Cilengitide completely suppressed invasion of collagen matrix by cells from H28 spheroids (three-dimensional cell clusters). Spheroids from the other cell lines were not strongly affected, although some inhibition was seen for MeT-5A and REN.
  • Knocking down ITGB5 with siRNA made most cell lines rounder and increased detachment, and it suppressed invasion by H28 spheroid cells.
  • ITGB5 knockdown with 1 nM siRNA substantially reduced αvβ5 expression but did not affect growth of the mesothelial and MPM cells. ITGB3 knockdown at the same dose did not affect H28 cell proliferation (results not shown).
  • In H28 cells, knocking down ITGB3 suppressed invasion more than knocking down ITGB5. The effect was similar in extent to cilengitide treatment.
  • In six primary mesothelioma cultures, cilengitide suppressed three-dimensional invasion in one sample, which expressed αvβ3. The authors did not show these results.
• The authors' conclusion: The authors concluded that cilengitide suppresses growth of MPM cells by promoting detachment, provided the cells are prone to anoikis. They also concluded that it suppresses invasiveness of cells with high target expression through antagonism of αvβ3 and αvβ5, and that integrins should be considered potential targets for MPM treatment.
• Limitations the authors state:
  • The authors stated it was unclear why ECM coating only partly protected H28 cells: this could be a difference of degree, or cilengitide could have additional anti-proliferative effects.
  • Higher siRNA concentrations did inhibit growth, but the authors stated it was not clear whether this was due to silencing ITGB3 or ITGB5.
  • The authors noted that αvβ3 expression in MPM is infrequent: they found it in only one of seven MPM cell lines.

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, Median Survival, Mesothelial Cells.

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