Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling

Our plain-English summary of Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling, by I. Dell'Anno, F. Morani, S. Patergnani, et al (Cancer Cell International, 2024).

The study

• Authors: I. Dell'Anno, F. Morani, S. Patergnani, A. Daga, P. Pinton, C. Giorgi, L. Mutti, F. Gemignani, S. Landi
• Journal: Cancer Cell International
• Published: 2024;24(1):226
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.

Methods: In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.

Results: After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca2+ homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).

Conclusions: Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.

© 2024. The Author(s).

In plain English

This laboratory and animal study tested thonzonium bromide (TB), a topical-use compound, against malignant pleural mesothelioma (MPM). It did not study asbestos exposure. Five MPM cell lines and one non-malignant mesothelial line (MeT-5A) were treated. After 24 hours, TB significantly suppressed ERK 1/2 phosphorylation, a cell-growth signal, in all lines except NCI-H28. It raised p38 phosphorylation in MeT-5A, Mero-14 and Ren cells. In Ren cells, TB first raised, then reduced, calcium signalling and mitochondrial respiration. By 72 hours it caused loss of mitochondrial membrane potential and more reactive oxygen species. Adding farnesol, but not geranylgeraniol, reversed TB's toxicity to the cells. Twenty female immunodeficient mice received human Ren mesothelioma cells in the abdomen. The 10 given TB survived longer than the 10 controls (P = 0.0076). By 7 weeks, all 10 controls and 5 of 10 treated mice had died. Imaging apparently showed no difference in tumour growth; the authors thought this likely reflected haemorrhagic ascites, more frequent in controls, affecting the signal. The authors noted that injected TB's toxicity needs careful study and systemic use would need new trials from phase 1.

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-line experiments plus an animal experiment (xenograft mouse model with survival analysis)
• Who was studied: Five malignant pleural mesothelioma cell lines (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one non-malignant SV40-immortalized mesothelial cell line (MeT-5A). Also 20 six-week-old female NOD-SCID (immunodeficient) mice injected intraperitoneally with luciferase-labelled human Ren MPM cells and split into two groups of 10.
• Exposure: The drug thonzonium bromide (TB): 1 µM in cell experiments; in mice, 4 mg/kg by intraperitoneal injection twice a week for four weeks starting from day 11, versus solvent in controls. No asbestos exposure was studied.
• Main results:
  • After 24 h, TB significantly suppressed ERK 1/2 phosphorylation in the cell lines, with NCI-H28 the only exception
  • TB enhanced p38 phosphorylation in the MeT-5A, Mero-14 and Ren cell lines
  • At 48 h, expression of the pro-apoptotic protein BAX was slightly increased in Mero-14, Mero-25 and Ren cells
  • In Ren cells, mitochondrial and cytosolic Ca2+ rose at 24 h, were similar to untreated cells at 48 h, and were significantly reduced at 72 h
  • In Ren cells, 72 h of TB treatment caused loss of mitochondrial membrane potential and increased reactive oxygen species production
  • In Ren cells, mitochondrial respiration and ATP production rose after 24 h of TB, then progressively fell at 48 h and were lost at 72 h
  • Adding farnesol (FOH) abolished TB's cytotoxic effect and significantly restored cell viability
  • Adding geranylgeraniol (GGOH) did not reduce TB's cytotoxicity; it enhanced it
  • In mice, overall survival was longer in the TB-treated group (n=10) than in the vehicle control group (n=10) (log-rank test, P = 0.0076)
  • By 7 weeks after cell inoculation, 10/10 vehicle-treated mice and 5/10 TB-treated mice had died
  • Tumour growth measured by bioluminescent imaging apparently did not change in either group. The authors attributed this likely to haemorrhagic ascites affecting the imaging, which was seen more often in the control group.
• The authors' conclusion: The authors concluded that the work provided some hints on biological mechanisms underlying TB's activity and evidence that TB is a candidate for new strategies against MPM. They hypothesized that TB affected tumour biology in the xenografted mice.
• Limitations the authors state:
  • The toxicity of TB given by intraperitoneal injection needs careful study
  • TB is approved in humans only for topical use; systemic use would require new experimentation starting from phase 1
  • Imaging-based tumour measurements were not used to judge efficacy, because peritoneal bleeding reduces bioluminescence values and leads to underestimation of tumour volume
  • Haemorrhagic ascites, seen more often in controls, likely affected the imaging comparison of tumour growth between groups

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, SV40, Mesothelial Cells, Apoptosis, Overall Survival, Kaplan-Meier Curve.

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