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Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma
Yasuhiro Nakajima1, Takeshi Kanno, Toshio Nagaya
1Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
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.
Insights
The adenosine deaminase (ADA) inhibitor EHNA shows promise for treating malignant pleural mesothelioma (MPM). EHNA induces apoptosis and suppresses tumor growth in MPM cells by increasing adenosine levels.
Area of Science:
- Oncology
- Pharmacology
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options.
- Investigating novel therapeutic targets for MPM is crucial.
Purpose of the Study:
- To evaluate the efficacy of the adenosine deaminase (ADA) inhibitor EHNA as a potential treatment for MPM.
- To elucidate the mechanism of action of EHNA in MPM cells.
Main Methods:
- In vitro studies using human MPM cell lines (MTT assay, TUNEL staining, Western blotting).
- Assessment of intracellular adenosine concentrations.
- In vivo studies in mice bearing MPM xenografts.
Main Results:
- EHNA induced apoptosis in MPM cell lines in a dose- and time-dependent manner.
- EHNA increased intracellular adenosine concentrations.
- EHNA suppressed tumor growth in vivo.
- The effects of EHNA were linked to adenosine accumulation and were blocked by an adenosine kinase inhibitor.
Conclusions:
- EHNA effectively induces apoptosis and inhibits proliferation of MPM cells by increasing intracellular adenosine.
- EHNA demonstrates therapeutic potential for the treatment of malignant pleural mesothelioma.
