Induction of metallothionein expression by supplementation of zinc induces resistance against platinum-based treatment in malignant pleural mesothelioma

Our plain-English summary of Induction of metallothionein expression by supplementation of zinc induces resistance against platinum-based treatment in malignant pleural mesothelioma, by M. Wyrich, H. Ohlig, M. Wessolly, et al (Translational Cancer Research, 2023).

The study

• Authors: M. Wyrich, H. Ohlig, M. Wessolly, E. Mairinger, J. Steinborn, L. Brcic, B. Hegedus, T. Hager, K. Greimelmaier, J. Wohlschlaeger, F.D. Mairinger, S. Borchert
• Journal: Translational Cancer Research
• Published: 2023;12(8):1929-1936
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth.

Methods: In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction.

Results: Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity.

Conclusions: MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.

2023 Translational Cancer Research. All rights reserved.

In plain English

This was a laboratory study of cells grown in dishes, not of patients. The authors tested three malignant pleural mesothelioma cell lines (NCI-H2052, NCI-H2452 and MSTO-211H) and one lung fibroblast cell line (MRC-5), which served as a control. Cells were given zinc sulfate at 10 to 90 µM, then the chemotherapy drug cisplatin at 10 µM. After 48 hours the authors measured apoptosis (programmed cell death), necrosis and viability. In a separate experiment, cells given zinc at 10, 40 or 70 µM were tested for expression of the metallothionein gene MT2A. MT2A expression rose at higher zinc doses, with about five-fold higher expression at 70 µM than at 40 µM. These trends had P values of 0.0833 for two cell lines and 1 for NCI-H2452, above the article's 0.05 significance cutoff. In all four cell lines, the apoptotic response to cisplatin fell as zinc rose: by 50% in MRC-5 and about 10% in NCI-H2452. The authors concluded that zinc reduced sensitivity to cisplatin. They speculated, without testing it, that heavy metals in cigarette smoke might act similarly in 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: In vitro laboratory experiment on cultured cell lines
• Who was studied: Three commercially obtained malignant pleural mesothelioma cell lines (NCI-H2052, NCI-H2452, MSTO-211H) and one lung fibroblast cell line (MRC-5), all from the American Type Culture Collection; no patients
• Exposure: Zinc sulfate at 10, 30, 50, 70 and 90 µM, followed 6 hours later by cisplatin at 10 µM for 48 hours. For the gene expression tests, zinc at 10, 40 and 70 µM for 48 or 77 hours. No asbestos exposure was studied.
• Main results:
  • In the mesothelioma cell lines, MT2A gene expression was higher at higher zinc doses, with about five-fold higher expression at 70 µM than at 40 µM zinc. The authors reported this in all three mesothelioma cell lines.
  • The P values for the rise in MT2A expression were 0.0833 for MSTO-211H, 1 for NCI-H2452 and 0.0833 for NCI-H2052. The article defined statistical significance as P of 0.05 or less after adjustment.
  • In cells treated with cisplatin, high zinc concentrations (70 to 90 µM) were followed by significantly less apoptosis. The decrease was dose-dependent in each tested cell line.
  • The largest drop in apoptosis was in the MRC-5 fibroblast control line, with a decline of 50%.
  • The smallest drop in apoptosis was in the NCI-H2452 mesothelioma line, at about 10%.
  • Apoptosis was negatively correlated with zinc concentration in all cell lines. The most linear decrease was in MRC-5 cells, with a Spearman correlation coefficient of minus 0.975.
• The authors' conclusion: The authors concluded that zinc induced MT2A expression in a dose-dependent manner and reduced the sensitivity of all the mesothelioma cell lines to cisplatin. They speculated that heavy metals such as cadmium in cigarette smoke might lead to early chemotherapy failure in patients who smoke, and said this has to be validated in further studies.
• Limitations the authors state:
  • Being an in vitro study, it could not assess effects of zinc on immune function.
  • Zinc balance in the body is incompletely understood, so laboratory results are difficult to transfer to living organisms.
  • The NCI-H2452 line showed very low apoptotic effects, which the authors attributed to possible other resistance mechanisms.
  • The suggested link between smoking and early chemotherapy failure was not tested and needs validation.

Topics

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

Related studies

• Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma — S. Borchert, P.M. Suckrau, et al. (2020)
• Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study — A. Mathilakathu, S. Borchert, et al. (2021)
• Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy — F.D. Mairinger, J. Schmeller, et al. (2018)
• An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity — A.R. Minchom, K. Saksornchai, et al. (2014)
• Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro — S. Borchert, M. Wessolly, et al. (2019)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)

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