Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma

Our plain-English summary of Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma, by G. Pasello, L. Urso, M. Silic-Benussi, et al (Journal of Thoracic Oncology, 2014).

The study

• Authors: G. Pasello, L. Urso, M. Silic-Benussi, M. Schiavon, I. Cavallari, G. Marulli, N. Nannini, F. Rea, V. Ciminale, A. Favaretto
• Journal: Journal of Thoracic Oncology
• Published: 2014;9(7):1008-1017
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is an aggressive, currently incurable tumor with increasing incidence in industrialized countries. Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (dulanermin) in combination with chemotherapy in MPM in vitro and in vivo.

Methods: In the present studies, we employed a panel of MPM cell lines to test the antitumor activity of recombinant human Apo2L/TRAIL (T) in combination with carboplatin and pemetrexed (CP) in vitro and SCID mice.

Results: Results demonstrated a significant increase of apoptosis in cell lines treated with CPT compared with those receiving CP or T as single agents. This synergistic effect was dependent on the ability of CP to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. The CPT combination was also effective in blocking the growth of MPM cell lines in a SCID mice preclinical model.

Conclusions: CPT increases MPM cell death in vitro and in vivo compared with CP. In vitro results suggest that chemotherapy sensitizes MPM to TRAIL-dependent apoptosis through p53 activation and subsequent upregulation of DRs.

In plain English

This was a laboratory study using cancer cells and mice. No patients were treated and asbestos exposure was not examined, although the authors used cells and tissue from patients. The authors tested recombinant human Apo2L/TRAIL (dulanermin), alone and with the chemotherapy drugs carboplatin and pemetrexed. They used seven malignant pleural mesothelioma cell lines (epithelioid, biphasic and sarcomatoid) and one sarcomatoid culture taken from a patient's tumor. TRAIL alone caused significant but uneven cell death in the mesothelioma cells. It caused no significant death in normal control cells. In ZL55 and ZL34 cells, the three-drug combination caused more cell death than chemotherapy or TRAIL alone (p less than 0.001). Chemotherapy raised levels of the protein p53 and of the TRAIL receptors DR4 and DR5. Blocking p53 reduced the extra cell death and the receptor increase. In mice with tumors from these two cell lines (6 per group), tumors were significantly smaller at day 21 with the combination than with chemotherapy alone. The authors concluded that the combination increased mesothelioma cell death in the lab and in mice compared with chemotherapy alone.

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 study: experiments on mesothelioma cell lines in culture (in vitro) plus an animal experiment in SCID mice carrying transplanted mesothelioma tumors
• Who was studied: Seven malignant pleural mesothelioma (MPM) cell lines: three epithelioid (ZL55, H28, M14K), three biphasic (ZL5, SPC111, MSTO-211H) and one sarcomatoid (ZL34). The study also used one short-term primary culture of sarcomatoid MPM cells from a patient's surgical specimen (MPM1801). Normal control cells were human foreskin fibroblasts and peripheral blood mononuclear cells from healthy donors. Five tumor tissues from MPM patients were tested for p53. Sixty male SCID mice were injected with ZL55 (30 mice) or ZL34 (30 mice) cells, and mice with measurable tumors were randomized into four treatment groups of 6. The work was done at the University of Padua and Istituto Oncologico Veneto, Italy.
• Exposure: Drug treatments, not asbestos. In the lab: carboplatin 27 uM plus pemetrexed 42 uM for 48 hours and/or rhApo2L/TRAIL (dulanermin) 50 ng/ml for 24 hours. In mice: carboplatin 75 mg/kg plus pemetrexed 100 mg/kg on day 1, rhApo2L/TRAIL 60 mg/kg on days 1, 2 and 3, or the combination, compared with untreated vehicle controls.
• Main results:
  • rhApo2L/TRAIL alone produced significant but uneven cell death across the MPM cell lines and the primary culture, regardless of tumor subtype. No significant death occurred in the normal control cells.
  • In the ZL34 (sarcomatoid) and ZL55 (epithelioid) cell lines, carboplatin and pemetrexed combined with TRAIL produced a significant synergistic increase in cell death (p < 0.001) compared with no treatment or with either treatment alone.
  • A similar effect was seen in all seven cell lines tested and in the sarcomatoid primary culture.
  • Treating ZL34 and ZL55 cells with the ROS scavenger N-acetyl-cysteine made no difference to cell death.
  • Carboplatin and pemetrexed raised p53 levels in ZL55 and ZL34 cells. Silencing p53 significantly reduced the cell death caused by the combination, and adding back wild-type p53 reversed this.
  • Five tumor tissues from MPM patients showed no or weak p53 expression.
  • Carboplatin and pemetrexed raised levels of the TRAIL receptors DR4 and DR5 in ZL55 and ZL34 cells. Silencing p53 significantly reduced this increase (p < 0.05).
  • In mice with ZL55 tumors, all three treatments (CP, T and CPT) reduced tumor volume at every time point compared with untreated mice. At day 21, tumor volume was significantly smaller with CPT than with CP (p < 0.05).
  • In mice with ZL34 tumors, T and CPT reduced tumor volume at every time point compared with untreated mice. At day 21, all three treatment groups differed significantly from untreated mice, and CPT differed significantly from CP. There was no significant difference between mice given CP and mice given T.
• The authors' conclusion: The authors concluded that the combination of carboplatin, pemetrexed and rhApo2L/TRAIL increased MPM cell death in vitro and in vivo compared with carboplatin and pemetrexed alone. They also concluded that their lab results suggest chemotherapy makes MPM cells more sensitive to TRAIL through p53 activation and increased DR4 and DR5 receptors. They suggested the drug might prove effective in treating 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: Necrosis, Apoptosis, Carboplatin, Pemetrexed (Alimta), Pleural Mesothelioma, Chemotherapy, Synergistic Effect.

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• A pathological complete response in malignant pleural mesothelioma after combination chemotherapy with Carboplatin and pemetrexed — S.C. Kao, B. McCaughan, et al. (2010)
• A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin — J.E. Gray, J.R. Infante, et al. (2015)
• Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer — H. Fujie, T. Tanaka, et al. (2011)
• Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma — M.J. Lathrop, E.K. Sage, et al. (2015)

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