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Updated: Dec 9, 2025
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma
Sze-Kwan Lam1, Sheng Yan1, Shi Xu1
1Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
Introduction:
Inhalation of asbestos fibers is the key culprit in malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM continues to increase globally due to the prolonged lag time in malignant transformation. The development of a novel adjuvant therapy for the minority of individuals with resectable early-stage disease and effective treatment for those with unresectable MPM are urgently needed. Our preliminary data revealed that ornithine decarboxylase (ODC) is highly expressed in MPM xenografts. This study aimed to determine the treatment effects of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in MPM xenografts.
Results:
In an "extended adjuvant DFMO treatment" setting, nude mice were fed with DFMO for 7 days prior to inoculation of 200,000 cells. DFMO suppressed tumor growth and increased median survival in both xenografts. In H226 xenograft, 43 % of treated mice had not reached the humane endpoint by day 132, mimicking long-term survival. DFMO decreased spermidine, increased nitrotyrosine and activated apoptosis in both xenografts. Furthermore, increase in nitrosocysteine, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesion and inhibition of the Akt/mTOR pathway were induced by DFMO in H226 xenograft. In "DFMO treatment" setting, 107 cells were inoculated into nude mice and DFMO treatment commenced when tumor size reached ∼50-100 mm3. DFMO also suppressed tumor growth by similar mechanisms. Supplementation with spermidine reversed the therapeutic effect of DFMO. DFMO increased actin nitration at tyrosine 53 and inhibited actin polymerization.
Conclusion:
DFMO is preclinically effective in treating MPM.
Insights
The drug α-difluoromethylornithine (DFMO) shows promise in treating malignant pleural mesothelioma (MPM) by inhibiting ornithine decarboxylase (ODC). This preclinical study found DFMO suppressed tumor growth and improved survival in MPM xenografts.
Area of Science:
- Oncology
- Biochemistry
- Drug Discovery
Background:
- Malignant pleural mesothelioma (MPM) incidence is rising globally despite asbestos restrictions due to long latency periods.
- Novel adjuvant and effective treatments are urgently needed for early-stage and unresectable MPM.
- Ornithine decarboxylase (ODC) is highly expressed in MPM, suggesting it as a therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in preclinical models of MPM xenografts.
- To investigate the mechanisms underlying DFMO's therapeutic effects in MPM.
Main Methods:
- Nude mice were treated with DFMO in extended adjuvant and direct treatment settings.
- Tumor growth, survival rates, and molecular markers (spermidine, nitrotyrosine, apoptosis, cytokines, DNA damage, Akt/mTOR pathway, actin nitration) were assessed.
- The effect of spermidine supplementation on DFMO efficacy was examined.
Main Results:
- DFMO significantly suppressed tumor growth and increased median survival in both MPM xenograft models.
- DFMO induced apoptosis, decreased spermidine levels, and increased nitrotyrosine.
- DFMO modulated inflammatory cytokines, induced DNA damage, inhibited the Akt/mTOR pathway, and affected actin polymerization.
Conclusions:
- DFMO demonstrates significant preclinical efficacy in treating malignant pleural mesothelioma.
- DFMO's mechanism involves ODC inhibition, polyamine depletion, and induction of cellular stress and apoptosis.
- Further investigation into DFMO as a therapeutic agent for MPM is warranted.
