Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells

Our plain-English summary of Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells, by D. Valenti, L. de Bari, G.A. Manente, et al (Biochimica et Biophysica Acta, 2013).

The study

• Authors: D. Valenti, L. de Bari, G.A. Manente, L. Rossi, L. Mutti, L. Moro, R.A. Vacca
• Journal: Biochimica et Biophysica Acta
• Published: 2013;1832(12):2085-96
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Increasing evidence reveals a large dependency of epithelial cancer cells on oxidative phosphorylation (OXPHOS) for energy production. In this study we tested the potential of epigallocatechin-3-gallate (EGCG), a natural polyphenol known to target mitochondria, in inducing OXPHOS impairment and cell energy deficit in human epitheliod (REN cells) and biphasic (MSTO-211H cells) malignant pleural mesothelioma (MMe), a rare but highly aggressive tumor with high unmet need for treatment. Due to EGCG instability that causes H2O2 formation in culture medium, the drug was added to MMe cells in the presence of exogenous superoxide dismutase and catalase, already proved to stabilize the EGCG molecule and prevent EGCG-dependent reactive oxygen species formation. We show that under these experimental conditions, EGCG causes the selective arrest of MMe cell growth with respect to normal mesothelial cells and the induction of mitochondria-mediated apoptosis, as revealed by early mitochondrial ultrastructure modification, swelling and cytochrome c release. We disclose a novel mechanism by which EGCG induces apoptosis through the impairment of mitochondrial respiratory chain complexes, particularly of complex I, II and ATP synthase. This induces a strong reduction in ATP production by OXPHOS, that is not adequately counterbalanced by glycolytic shift, resulting in cell energy deficit, cell cycle arrest and apoptosis. The EGCG-dependent negative modulation of mitochondrial energy metabolism, selective for cancer cells, gives an important input for the development of novel pharmacological strategies for MMe.

© 2013 Elsevier B.V. All rights reserved.

In plain English

This was a laboratory study on human cells grown in dishes, not on people or animals. It did not study asbestos exposure. The authors tested epigallocatechin-3-gallate (EGCG), a compound from green tea, on two malignant pleural mesothelioma cell lines and on normal mesothelial cells. The cancer lines were REN (epithelioid) and MSTO-211H (biphasic); the normal line was MET5A. EGCG breaks down in culture medium and forms hydrogen peroxide, so it was mostly given with two enzymes (superoxide dismutase and catalase) to stabilize it. Without the enzymes, EGCG inhibited growth of both cancer and normal cells. With them, EGCG inhibited REN cell growth (estimated IC50, the dose that halved growth, of 100 μM) but did not affect MET5A cells. In REN cells, stabilized EGCG cut the activity of mitochondrial energy-producing complexes by about 50% at 18 to 24 hours. It also lowered cellular ATP (energy) by 50%, about tripled the share of cells stalled in the G2/M phase of the cell cycle, and increased programmed cell death. MSTO-211H cells responded similarly. The authors concluded that EGCG may provide therapeutic options for 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) study on human cell lines
• Who was studied: Human cell lines: REN (epithelioid malignant mesothelioma, the main model), MSTO-211H (biphasic mesothelioma) and MET5A (normal mesothelial cells); no human subjects
• Exposure: EGCG from 20 to 200 μM for 24 h, with or without superoxide dismutase (5 units/ml) and catalase (30 units/ml). Time-course experiments used 100 μM EGCG plus both enzymes. Asbestos was not studied.
• Main results:
  • In REN mesothelioma cells treated with EGCG plus superoxide dismutase and catalase, growth was inhibited in a dose-dependent manner, with an estimated IC50 of 100 μM
  • In normal MET5A cells, viability was not affected by EGCG given with superoxide dismutase and catalase
  • Without superoxide dismutase and catalase, EGCG inhibited growth of both REN and MET5A cells
  • In REN cells after 24 h with 100 μM stabilized EGCG, cellular ATP was 50% lower than in untreated cells
  • In REN cells after 18 to 24 h, the share of surviving cells in the G2/M phase of the cell cycle increased about 3-fold compared with untreated cells
  • In REN cells, the activity of all mitochondrial respiratory chain complexes was reduced by about 50% at 18 to 24 h after treatment
  • In REN cells, cytochrome c (a signal for cell death) began leaving the mitochondria 6 h after EGCG was added and reached about 3-fold control levels in the cytosol at 24 h
  • In REN cells, STAT3 protein level fell by 50% starting 3 h after EGCG treatment, compared with untreated cells
  • In MSTO-211H cells, apoptosis increased 1.6-fold at 24 h and 3-fold at 48 h after EGCG treatment, compared with untreated cells
  • In normal MET5A cells given 100 μM stabilized EGCG, no change in mitochondrial complex activities or cellular ATP was observed (data not shown in the article)
• The authors' conclusion: The authors concluded that EGCG, and other agents that inhibit mitochondrial respiratory chain activity and energy metabolism, may provide therapeutic options for managing malignant mesothelioma. They suggested EGCG be tested as an add-on to other chemotherapy in early clinical trials.
• Limitations the authors state:
  • With unstabilized EGCG, the authors could not be sure whether cell death, including in normal cells, was caused by EGCG itself or by its breakdown products
  • Further studies are needed to check whether the drop in STAT3 is linked to the impairment of mitochondrial complexes

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Pleural Mesothelioma, Biphasic Mesothelioma, Superoxide, Reactive Oxygen Species (ROS), Mesothelial Cells.

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