Glutathione S-transferase P1-1 as a target for mesothelioma treatment

Our plain-English summary of Glutathione S-transferase P1-1 as a target for mesothelioma treatment, by A. De Luca, F. Pellizzari Tregno, A. Sau, et al (Cancer Science, 2013).

The study

• Authors: A. De Luca, F. Pellizzari Tregno, A. Sau, A. Pastore, C. Palumbo, A. Alama, R. Cicconi, G. Federici, A.M. Caccuri
• Journal: Cancer Science
• Published: 2013;104(2):223-30
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum(II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO-211H, MPP89, MM-B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC(50) values in the low micromolar range (IC(50) between 1 and 4 μM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy.

© 2012 Japanese Cancer Association.

In plain English

This was a laboratory study of human mesothelioma cells grown in culture. It did not involve patients and did not study asbestos exposure. The authors tested NBDHEX, an experimental compound that blocks the enzyme glutathione S-transferase, on four malignant mesothelioma cell lines. MPP89 had the epithelioid form and the other three the biphasic form. All four lines had high levels of the enzyme form GSTP1-1. After 48 hours, the NBDHEX concentration that halved cell growth was 1.0 to 4.0 micromolar, versus 2.0 to 7.0 micromolar for the chemotherapy drug cisplatin. NBDHEX was more toxic than cisplatin in two lines and about equally toxic in the other two. NBDHEX activated the JNK and p38 signalling proteins in all four lines. After 15 hours, 53%, 59% and 80% of cells were apoptotic (undergoing programmed cell death) in MPP89, MSTO-211H and MM-B1, but only 6% in Mero 48a. Given simultaneously with cisplatin, NBDHEX had synergistic effects in MM-B1, MPP89 and Mero 48a. In MSTO-211H, an additive-synergistic effect was seen when NBDHEX was given first. The authors concluded that NBDHEX was effective alone or with cisplatin in these cells.

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 human mesothelioma cell lines
• Who was studied: Four human malignant mesothelioma cell lines: MPP89 (epithelioid) and MSTO-211H, MM-B1 and Mero 48a (biphasic). The MCF7 breast cancer cell line was used as a negative control for GSTP1-1. No patients were studied.
• Exposure: The experimental glutathione S-transferase inhibitor NBDHEX and the chemotherapy drug cisplatin (CDDP), each alone and in combination, at a range of concentrations. Equitoxic NBDHEX doses were 10, 8, 8 and 15 micromolar for MSTO-211H, MM-B1, Mero 48a and MPP89. Asbestos exposure was not studied.
• Main results:
  • All four mesothelioma cell lines showed high expression of GSTP1-1.
  • The concentration giving 50% growth inhibition (IC50) after 48 hours was 1.0 to 4.0 micromolar for NBDHEX and 2.0 to 7.0 micromolar for cisplatin. Table means, NBDHEX vs cisplatin: MSTO-211H 1.5 vs 2.0; MM-B1 1.3 vs 5.7; Mero 48a 1.3 vs 6.5; MPP89 3.9 vs 3.6.
  • NBDHEX was more cytotoxic than cisplatin in Mero 48a and MM-B1 cells, and about equally cytotoxic in MSTO-211H and MPP89.
  • Caspase-3 activation was evident in MSTO-211H and MM-B1, lower in MPP89 and negligible in Mero 48a.
  • After 15 hours of NBDHEX treatment, the overall percentage of apoptotic cells was 53% in MPP89, 59% in MSTO-211H and 80% in MM-B1.
  • Mero 48a cells showed only a negligible amount of apoptosis (6%).
  • Experiments with a caspase inhibitor in MSTO-211H, MM-B1 and MPP89 indicated that NBDHEX-induced cell death depended on caspases.
  • NBDHEX caused a rapid and sustained increase in the active forms of JNK and p38 in all four lines.
  • Oxidative imbalance was mild in most lines but marked in MM-B1 and MPP89.
  • Giving NBDHEX and cisplatin at the same time produced strong synergism in MM-B1 and MPP89 and synergism in Mero 48a.
  • In MSTO-211H cells, an additive-synergistic effect was seen when NBDHEX was given before cisplatin.
• The authors' conclusion: The authors concluded that NBDHEX was effective as a single agent, or in combination with cisplatin to increase that drug's cytotoxicity. They suggested it could potentially be used to increase the therapeutic index of cisplatin in mesothelioma patients.
• Limitations the authors state:
  • The authors noted that the response of MPP89 and MM-B1 cells to NBDHEX appeared more complex and possibly involved additional pathways.

Topics

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

Medical terms in this study, explained in our Lexicon: Glutathione (GSH), Mesothelioma, Pleural Mesothelioma, Epithelioid, Biphasic Mesothelioma, Apoptosis, Oxidative Stress, Cisplatin.

Related studies

• Vitamin C levels in blood are influenced by polymorphisms in glutathione S-transferases — A. Horska, C. Mislanova, et al. (2011)
• Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California — S.J. London, A.K. Daly, et al. (1995)
• Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, S.T. Saarikoski, et al. (1996)
• Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies — M. Dusinska, M. Staruchova, et al. (2012)
• Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma — S. Landi, F. Gemignani, et al. (2007)
• Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers — K. Jakobsson, A. Rannug, et al. (1994)

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