Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma

Our plain-English summary of Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma, by Y. Nakajima, T. Kanno, T. Nagaya, et al (Cellular Physiology and Biochemistry, 2015).

The study

• Authors: Y. Nakajima, T. Kanno, T. Nagaya, K. Kuribayashi, T. Nakano, A. Gotoh, T. Nishizaki
• Journal: Cellular Physiology and Biochemistry
• Published: 2015;35(1):51-60
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background/aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment.

Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells.

Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells.

Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

© 2015 S. Karger AG, Basel.

In plain English

This laboratory study, by researchers at Hyogo College of Medicine in Japan, tested EHNA, a drug that blocks the enzyme adenosine deaminase (ADA), against malignant pleural mesothelioma (MPM). It did not study asbestos exposure or patients. The authors treated four human MPM cell lines (NCI-H28, NCI-H2052, NCI-H2452 and MSTO-211H) with EHNA at 0.01 to 1 mM for 24 to 48 hours. EHNA reduced cell survival more at higher doses and longer times, to below 20% of untreated levels at 1 mM for 48 hours, and increased signs of programmed cell death (apoptosis). Lung and liver cancer cell lines responded similarly. Another ADA blocker, pentostatin, had little or no effect on the survival of the MPM cells. EHNA raised adenosine levels inside MPM cells. Silencing the ADA gene also reduced MPM cell survival, and the drug ABT-702 prevented this. In mice with NCI-H2052 tumors under the skin, EHNA (0.3 mg/kg, injected three times a week) reduced tumor growth compared with control mice. The authors concluded this may offer a new treatment strategy for MPM. They noted that an unknown additional mechanism may be involved.

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 using cultured human cancer cell lines, plus an animal experiment in mice
• Who was studied: Four human MPM cell lines (NCI-H28, NCI-H2052, NCI-H2452, MSTO-211H). For comparison, human lung cancer lines (A549, SBC-3, Lu-65) and hepatic cancer lines (HepG2, HuH-7). Male nude KSN/Slc mice, 7 weeks old, with NCI-H2052 cells implanted under the skin; the tumor-growth figure reports n=6 mice. Work was done at Hyogo College of Medicine, Japan.
• Exposure: No asbestos exposure was studied. Cells were treated with the ADA inhibitor EHNA (0.01-1 mM, 24-48 h) and, for comparison, with pentostatin. ADA was also silenced with siRNA, with or without the adenosine kinase inhibitor ABT-702 (10 nM). Mice received intraperitoneal EHNA at 0.3 mg/kg or PBS three times a week.
• Main results:
  • In the four MPM cell lines, EHNA reduced cell viability in a concentration- and time-dependent manner, to below 20% of basal levels after 48 hours at 1 mM.
  • EHNA (1 mM) increased TUNEL-positive (apoptotic) cells compared with untreated controls in all MPM cell lines tested.
  • EHNA also reduced viability of the human lung and hepatic cancer cell lines.
  • The other ADA inhibitor, pentostatin, had little or no effect on viability of the MPM cell lines.
  • EHNA (0.3 mM) increased adenosine inside MPM cells over 3-9 hours. Adenosine outside the cells did not increase or decreased.
  • Silencing ADA reduced MPM cell viability, and this cell death was prevented by the adenosine kinase inhibitor ABT-702.
  • In mice with NCI-H2052 tumors, EHNA at 0.3 mg/kg reduced tumor growth compared with PBS-injected control mice. Exact tumor volumes are shown only in a figure, not in the text.
• The authors' conclusion: The authors concluded that EHNA induces apoptosis of MPM cells and suppresses tumor growth in mice inoculated with NCI-H2052 cells, and that this may provide a new strategy for MPM treatment.
• Limitations the authors state:
  • Because pentostatin had little or no effect, the authors stated that EHNA's effect may not come simply from raising adenosine levels, and that an unknown additional mechanism may be involved.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis, Neoplasm.

Related studies

• Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma — Y. Nakajima, K. Kuribayashi, et al. (2020)
• AMP converted from intracellularly transported adenosine upregulates p53 expression to induce malignant pleural mesothelioma cell apoptosis — Y. Nogi, T. Kanno, et al. (2012)
• Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo — S. Miyoshi, H. Hamada, et al. (2012)
• Bruton's Tyrosine Kinase Inhibitor Attenuates Warm Hepatic Ischemia/Reperfusion Injury via Modulation of the NLR Family Pyrin Domain Containing 3 Inflammasome — S.H. Song, F. Liu, et al. (2020)
• Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma — Y. Kaku, H. Nagaya, et al. (2014)
• ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity — K.I. Sakata, K. Maeda, et al. (2020)

Browse more research in Cellular Physiology and Biochemistry, or return to medical research.