Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma

Abstract

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.

Keywords: Apoptosis; Malignant pleural mesothelioma; Ornithine decarboxylase; Spermidine; Xenografts; α-difluoromethylornithine (DFMO).