Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

Our plain-English summary of Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin, by L.L. Belyanskaya, T.M. Marti, S. Hopkins-Donaldson, et al (Molecular Cancer, 2007).

The study

• Authors: L.L. Belyanskaya, T.M. Marti, S. Hopkins-Donaldson, S. Kurtz, E. Felley-Bosco, R.A. Stahel
• Journal: Molecular Cancer
• Published: 2007;6:66
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.

Results: We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine.

Conclusion: Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

In plain English

This was a laboratory study of malignant pleural mesothelioma (MPM) cells grown in dishes. It did not involve patients and did not study asbestos exposure. The authors tested 13 MPM cell lines or primary cultures against TRAIL, a protein that can trigger cell death, and two lab-made antibodies: Mapatumumab, which targets the TRAIL-R1 receptor, and Lexatumumab, which targets TRAIL-R2. They then tested the antibodies, but not TRAIL, with the chemotherapy drug cisplatin in selected cell lines. With TRAIL, seven cell lines were sensitive, two partially resistant and four resistant. Six of the 13 were more sensitive to Lexatumumab, two to Mapatumumab, two showed similar sensitivity to both, and three were almost completely resistant to both. Sensitivity was not related to how much receptor the cells carried. In several cell lines, cisplatin and the antibodies together acted synergistically, meaning more than expected from each alone. In H226 cells, adding either antibody after cisplatin did not significantly increase cell death. In H28 cells, giving cisplatin first worked better than giving an antibody first. The antioxidant N-acetylcysteine reduced cell death from cisplatin alone and with Mapatumumab. The authors concluded that cisplatin followed by either antibody deserves investigation in MPM patients.

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 human mesothelioma cell lines and primary cultures
• Who was studied: 13 human malignant pleural mesothelioma cell lines or primary cultures. Five cell lines and three primary cultures (SDM4, SDM6, SDM13) were generated in the authors' Zürich laboratory, and five cell lines were obtained from ATCC. Jurkat leukemia cells were used as a positive control.
• Exposure: No asbestos exposure was studied. Cells were treated with recombinant TRAIL (100 ng/ml for 72 h) and with the agonistic antibodies Mapatumumab (anti-TRAIL-R1) and Lexatumumab (anti-TRAIL-R2) at 0.01 to 10 µg/ml. In selected cell lines, cisplatin was combined with the antibodies, not with TRAIL, in different sequences. The antioxidant N-acetylcysteine was also tested.
• Main results:
  • With TRAIL, seven of the 13 cell lines were sensitive (more than 60% cell death), two (SDM13, SDM6) were partially resistant (20 to 60% cell death), and four (H2052, SPC212, ZL34, H226) were resistant (less than 20% cell death).
  • The level of TRAIL death receptor on the cells did not correlate with sensitivity to TRAIL.
  • Six of the 13 cell lines (46%) were more sensitive to Lexatumumab than to Mapatumumab. Two were more sensitive to Mapatumumab, and two showed similar sensitivity to both.
  • Three cell lines (H2052, SPC212, H226) showed almost complete resistance to both antibodies at 10 µg/ml.
  • In H226 cells, 2 µM cisplatin alone caused 29% cell death. Adding either antibody 24 h later did not significantly increase the dead cell fraction.
  • In ZL55 cells, cisplatin and the antibodies showed a synergistic effect.
  • In ZL5 cells given cisplatin and Lexatumumab at the same time, higher doses reduced cell growth synergistically, with combination index values below 0.6. Lower doses showed no detectable synergy.
  • In H28 cells, giving Mapatumumab or Lexatumumab before cisplatin did not significantly enhance cell killing, even with up to 24 h between treatments.
  • In H28 cells, cisplatin given first, followed by Mapatumumab or Lexatumumab, reduced cell viability by 69% and 73% respectively after 24 h.
  • In the ZL55, H28 and ZL34 cell lines, the antioxidant N-acetylcysteine significantly reduced cell death caused by cisplatin and by cisplatin combined with Mapatumumab.
• The authors' conclusion: The authors concluded that giving cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Malignant Mesothelioma, Cisplatin, Pleural Mesothelioma, Multimodal Therapy, Prognosis, Necrosis, Monoclonal.

Related studies

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• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)
• Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma — A. Baldi, M.T. Piccolo, et al. (2011)
• Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines — Y. Wang, A.K. Rishi, et al. (2010)
• Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL — T. Tatsuta, M. Hosono, et al. (2014)

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