Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies

Our plain-English summary of Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies, by P. Icard, X.D. Zhang, E. Lemoisson, et al (Journal of Bioenergetics and Biomembranes, 2012).

The study

• Authors: P. Icard, X.D. Zhang, E. Lemoisson, M.H. Louis, S. Allouche, H. Lincet, L. Poulain
• Journal: Journal of Bioenergetics and Biomembranes
• Published: 2012;44(1):81-90
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the "Warburg effect", to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.

In plain English

This laboratory study, which the authors describe as a synthesis of their work, tested the chemical 3-bromopyruvate (3-BrPA), a substance meant to disrupt cancer cells' energy supply, against mesothelioma. It did not study asbestos exposure. Two human malignant mesothelioma cell lines, MSTO-211H and NCI-H28, were grown in the laboratory, and their responses differed. Added after 24 hours of culture, 3-BrPA was not clearly toxic to MSTO-211H cells but killed NCI-H28 cells. At 200 μM for 72 hours, around 90% of NCI-H28 cells disappeared. Signs of programmed cell death were seen in both lines, and Mcl-1, a protein that helps cells resist death, decreased in both. In nude mice given human mesothelioma cells into the abdomen (12 per group), two series of four injections of 3-BrPA prolonged survival (p less than 0.0001). One series alone, or cisplatin alone, had no effect, but cisplatin plus one series prolonged survival. The authors called for toxicity studies and for clinical study in pleural or peritoneal mesothelioma, especially combined with cisplatin.

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 cultured cancer cell lines and on mice), presented as a synthesis of the authors' work
• Who was studied: two human malignant mesothelioma cell lines (MSTO-211H and NCI-H28) obtained from the American Type Culture Collection; also female nude CD1 mice aged 4 to 6 weeks that developed peritoneal tumours after abdominal injection of MSTO-211H cells
• Exposure: the experimental drug 3-bromopyruvate (3-BrPA), alone and combined with cisplatin (no asbestos exposure was studied)
• Main results:
  • When 3-BrPA was added after 24 h of culture, it was not evidently cytotoxic to MSTO-211H cells
  • In NCI-H28 cells, 3-BrPA was strongly cytotoxic; at 72 h, 200 μM led to the disappearance of around 90% of cancer cells
  • In both cell lines, PARP cleavage showed apoptosis occurred before 72 h at 150 and 200 μM
  • At 200 μM, expression of the anti-apoptotic protein Mcl-1 clearly decreased in both lines after 72 h
  • When lower doses were given from the start of culture, dose-dependent cytotoxicity was seen in both lines, more so in MSTO-211H
  • MSTO-211H cells had normal mitochondrial respiration; NCI-H28 cells had clearly decreased mitochondrial respiration
  • In mice (12 per group), survival was significantly prolonged (p<0.0001) with two series of four weekly abdominal injections of 3-BrPA starting at day 21
  • In mice, a single series of four 3-BrPA injections, or a single cisplatin injection (4 mg per kg) at 21 days, had no effect on survival
  • In mice, cisplatin combined with 3-BrPA led to a highly significant prolongation of survival
• The authors' conclusion: The authors concluded that clinical studies of 3-BrPA should be considered for patients with advanced pleural or peritoneal mesothelioma, with particular attention to combining it with cisplatin
• Limitations the authors state:
  • A cell-death pathway other than apoptosis, such as necrosis, could not be excluded, particularly in NCI-H28 cells
  • NCI-H28 cells could not be grown as tumours in mice, so 3-BrPA was tested in mice only on MSTO-211H tumours
  • The toxicity of 3-BrPA had not been studied

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cisplatin, Necrosis, Peritoneal Mesothelioma.

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