Cisplatin in combination with Phenethyl Isothiocyanate (PEITC), a potential new therapeutic strategy for malignant pleural mesothelioma

Our plain-English summary of Cisplatin in combination with Phenethyl Isothiocyanate (PEITC), a potential new therapeutic strategy for malignant pleural mesothelioma, by I. Denis, L. Cellerin, M. Gregoire, et al (Oncotarget, 2014).

The study

• Authors: I. Denis, L. Cellerin, M. Gregoire, C. Blanquart
• Journal: Oncotarget
• Published: 2014;5(22):11641-52
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a very aggressive form of cancer with a poor diagnosis and prognosis. The first line treatment for MPM is a combination of cisplatin and Pemetrexed, which displayed limited efficacy and severe side effects. The naturally occurring compound phenethyl isothiocyanate (PEITC) previously showed interesting anti-tumor properties on several cancer cell lines. We thus aim at evaluating PEITC used alone or in combination with cisplatin in order to improve MPM treatment. Nine MPM cell lines and primary mesothelial cells (PMC), co-cultured or not with M2 macrophages present in MPM microenvironment, were used to assess PEITC and cisplatin anti-tumor properties. Compounds were used alone or in combination. Both PEITC and cisplatin were cytotoxic on MPM cells in a dose dependent manner. We herein showed that PEITC-induced cytotoxicity was due to the generation of reactive oxygen species. Moreover, we showed that cisplatin-PEITC combination allowed the potentialization of both compounds' cytotoxic effects and prevented the emergence of resistant MPM cells. Interestingly, PMC were not sensitive to the combination. Finally, we showed that M2 macrophages did not alter the anti-tumor properties of the combination. Cisplatin-PEITC combination thus represents a promising strategy to induce a selective toxicity towards malignant cells.

In plain English

This was a laboratory study on cells grown in dishes, not on patients or asbestos exposure. Researchers in Nantes, France, tested cisplatin, a chemotherapy drug, and phenethyl isothiocyanate (PEITC), a compound from cruciferous vegetables. They used each drug alone and the two together on nine malignant pleural mesothelioma cell lines grown from patients' pleural fluid, and on purchased normal mesothelial cells of peritoneal origin. Both drugs killed more mesothelioma cells as the dose rose. Adding an antioxidant (NAC) reduced PEITC's cell killing and reactive oxygen species, which the authors took as evidence that PEITC worked through reactive oxygen species. After 72 hours, cisplatin plus 6 µM PEITC caused almost 80% cell death, compared with about 40% for each drug alone. After 9 days of repeated treatment, about 28% of cells remained viable with cisplatin alone and 47% with PEITC alone, but less than 5% with the combination. Normal mesothelial cells were not affected in viability tests. When grown with M2 macrophages (a type of immune cell), they seemed more sensitive at the higher PEITC dose. The authors concluded that the combination could represent a promising strategy for treating mesothelioma.

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) cell culture experiments: viability, cell-death, reactive oxygen species, DNA-damage, clonogenic and co-culture assays
• Who was studied: Nine malignant pleural mesothelioma cell lines (Meso4, 11, 13, 34, 47, 56, 76, 96, 152) established from patients' pleural fluids at a laboratory in Nantes, France. Also commercially purchased primary mesothelial cells of peritoneal origin, some co-cultured with M2 macrophages. No dates given.
• Exposure: Drug treatments: PEITC (for example 2, 4 and 6 µM) and cisplatin (for example 0.8 mg/L), alone or combined, with or without the antioxidant NAC. Asbestos exposure was not studied.
• Main results:
  • In three mesothelioma cell lines, the PEITC IC50 (the dose that halves cell viability) was 7.4 plus or minus 0.2 µM.
  • Co-treatment with NAC reduced (in the article's words, inhibited) PEITC-induced cell killing. The authors said this suggested a role for reactive oxygen species.
  • With NAC, both reactive oxygen species generation and cell killing by PEITC decreased. The authors said this strongly suggested a causative link.
  • In the same mesothelioma cell lines, the cisplatin IC50 was 1.8 plus or minus 0.21 mg/L.
  • At the highest cisplatin dose (25 mg/L), almost 40% of mesothelioma cells died, but no reactive oxygen species were detected.
  • The DNA-damage marker P-H2A.X was not seen with cisplatin alone, but the combination strongly enhanced it in mesothelioma cells.
  • After 72 hours, cisplatin plus 6 µM PEITC caused almost 80% mesothelioma cell death, compared with about 40% for each compound alone.
  • After 9 days of repeated treatment of mesothelioma cells, about 28% of cells were viable with cisplatin alone, 47% with PEITC alone, and less than 5% with the combination.
  • In six additional mesothelioma cell lines, three (Meso13, Meso34, Meso56) showed strong resistance to cisplatin or PEITC alone after the second treatment.
  • In all six additional cell lines, the combination left less than 10% viable cells after 9 days.
  • Primary mesothelial cells were not affected by either compound alone or by the combination over 72 hours.
  • With M2 macrophages present, primary mesothelial cells seemed sensitized at the higher PEITC dose. Cisplatin with 4 µM PEITC remained non-toxic to them while being highly toxic to mesothelioma cells.
• The authors' conclusion: The authors concluded that cisplatin with PEITC induces strong mesothelioma cell death while remaining safe for primary mesothelial cells, with limited emergence of resistance compared with either drug alone. They said it could represent a promising strategy for treating malignant pleural mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Prognosis, Pemetrexed (Alimta), Mesothelial Cells, Macrophage, Reactive Oxygen Species (ROS).

Related studies

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• In vitro anti-mesothelioma activity of cisplatin-gemcitabine combinations: evidence for sequence-dependent effects — I. Zanellato, C.D. Boidi, et al. (2011)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• ADP sensitizes ZL55 cells to the activity of cisplatin — A. Muscella, L.G. Cossa, et al. (2019)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)
• High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with (99m)Tc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin — O. Arrieta, L.A. Medina, et al. (2014)

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