A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma

Our plain-English summary of A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma, by S. Nishikawa, A. Tanaka, A. Matsuda, et al (Cancer Medicine, 2014).

The study

• Authors: S. Nishikawa, A. Tanaka, A. Matsuda, K. Oida, H. Jang, K. Jung, Y. Amagai, G. Ahn, N. Okamoto, S. Ishizaka, H. Matsuda
• Journal: Cancer Medicine
• Published: 2014;3(2):416-25
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chronic inflammation due to the absorption of asbestos is an important cause of mesothelioma. Although the increased prevalence of mesothelioma is a serious problem, the development of effective chemotherapeutic agents remains incomplete. As the nuclear factor-κB (NF-κB) pathway contributes to malignant transformation of various types of cells, we explored NF-κB activity in three different pathological types of malignant mesothelioma cells, and evaluated the therapeutic potential of a recently reported NF-κB inhibitor, IMD-0354. NF-κB was constantly activated in MSTO-211H, NCI-H28, and NCI-H2052 cells, and the proliferation of these cell lines was inhibited by IMD-0354. D-type cyclins were effectively suppressed in mixed tissue type MSTO-211H, leading to cell cycle arrest at sub G1 /G1 phase. IMD-0354 reduced cyclin D3 in both epithelial tissue type NCI-H28 and sarcomatoid tissue type NCI-H2052. In a sphere formation assay, IMD-0354 effectively decreased the number and diameter of MSTO-211H spheres. Preincubation of MSTO-211H cells with IMD-0354 delayed tumor formation in transplanted immunodeficient mice. Furthermore, administration of IMD-0354 markedly rescued the survival rate of mice that received intrathoracic injections of MSTO-211H cells. These results indicate that a targeted drug against NF-κB might have therapeutic efficacy in the treatment of human malignant mesothelioma.

© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This laboratory study used cells and mice, not people, and tested no asbestos exposure. The authors studied three human malignant mesothelioma cell lines: MSTO-211H (mixed tissue type), NCI-H28 (epithelial tissue type) and NCI-H2052 (sarcomatoid tissue type). They tested IMD-0354, an experimental drug that blocks a signaling protein called NF-κB, alongside the cancer drugs cisplatin and pemetrexed. NF-κB was active in all three lines. IMD-0354 reduced that activity and slowed cell growth; the authors identified no additive effect when it was combined with cisplatin or pemetrexed. It held more cells at an early stage of cell division and lowered cyclin D3, a growth-related protein, in all three lines, but did not markedly increase apoptosis (programmed cell death) in a 24-hour TUNEL test. MSTO-211H cells treated with the drug before injection under the skin of eight mice formed tumors that grew more slowly. Among 15 mice given chest injections of cancer cells, those treated daily with IMD-0354 or cisplatin (five each) survived significantly longer than five given salt solution. The authors concluded that IMD-0354 is a potential therapeutic agent 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 study of human mesothelioma cell lines, plus two mouse transplantation (xenograft) experiments
• Who was studied: Three commercially obtained human malignant mesothelioma cell lines: MSTO-211H (mixed tissue type), NCI-H2052 (sarcomatoid tissue type) and NCI-H28 (epithelial tissue type). Also eight female BALB/c nude mice (subcutaneous model) and 15 SCID mice (chest-cavity model). The work was done at Tokyo University of Agriculture and Technology, Japan.
• Exposure: No asbestos exposure was studied. The treatment tested was IMD-0354, an inhibitor of IKKβ that blocks NF-κB activation. It was given at various concentrations to cells and at 10 mg/kg daily by injection into the abdomen in mice. It was compared with cisplatin (2 mg/kg daily in mice) and pemetrexed (cells only).
• Main results:
  • NF-κB was active in untreated cells of all three lines. IMD-0354 reduced it in a concentration-dependent way, and 2.5 µmol/L completely removed the nuclear NF-κB p65 subunit in MSTO-211H and NCI-H2052 cells.
  • After 48 hours, IMD-0354 significantly suppressed growth of MSTO-211H and NCI-H2052 cells, as cisplatin and pemetrexed also did. NCI-H28 growth was significantly suppressed at 2.5 µmol/L IMD-0354.
  • The authors identified no additive effect on cell growth when IMD-0354 was combined with pemetrexed or cisplatin, in any of the three cell lines.
  • In all three cell lines, 1.25 µmol/L IMD-0354 for 24 hours significantly increased the share of cells at the subG1/G1 phase and decreased the share at the S phase.
  • In the TUNEL test for apoptosis, IMD-0354 did not markedly increase the percentage of apoptotic (TUNEL-positive) cells within 24 hours.
  • Cyclin D3 decreased significantly in all three lines, and cyclins D1 and D2 also decreased in MSTO-211H. In NCI-H2052, cyclins D1 and D2 increased, and in NCI-H28 cyclin D1 increased. The protein Bcl-2 decreased only in NCI-H2052.
  • Only MSTO-211H cells formed spheres under serum deprivation, and IMD-0354 suppressed sphere formation in a concentration-dependent way.
  • In eight nude mice, tumors from MSTO-211H cells pretreated overnight with IMD-0354 grew more slowly than tumors from untreated cells injected into the same mice.
  • In 15 SCID mice given chest-cavity injections of MSTO-211H cells, the groups treated daily with IMD-0354 (five mice) or cisplatin (five mice) survived significantly longer than the PBS-treated group (five mice). Survival did not differ significantly between the IMD-0354 and cisplatin groups.
• The authors' conclusion: The authors concluded that IMD-0354 is a potential therapeutic agent for mesothelioma. They also suggested a possible role in preventing mesothelioma in people seriously exposed to asbestos, although prevention was not tested in this study.

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: Malignant Mesothelioma, Chronic Inflammation, Mesothelioma, Malignant Transformation, Sarcomatoid, Intrathoracic.

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