OXTR targeted local therapy could be a promising strategy for pleural mesothelioma

Introduction Mesothelioma is one of the most aggressive neoplasms worldwide and has an extremely poor prognosis. We have previously discovered that oxytocin receptors (OXTR) are highly expressed in mesothelioma and OXTR knockdown significantly decreases the proliferation of mesothelioma cells with high- OXTR expression by disturbing the tumor cell cycle. Furthermore, the OXTR inhibitor, cligosiban, demonstrated antitumor efficacy in vivo. However, systemic administration required high doses, raising concerns about systemic toxicity. Therefore, we explored a local treatment strategy using intrathoracic drug delivery, and developed a dissolved formulation of cligosiban to enhance drug accumulation. Methods To establish a treatment method for localized control via trans-thoracic administration against pleural mesothelioma, the antitumor effect of a dissolved cligosiban in levulinic acid was evaluated in several mesothelioma cell lines. For in vivo analysis, an intrathoracic mesothelioma xenograft model was established with nude mice, and the therapeutic efficacy of intrathoracic administration of the dissolved cligosiban was examined. Results In vitro, dose-response experiments in two mesothelioma cell lines with high- OXTR expression demonstrated significant concentration-dependent changes in cell viability at micromolar concentrations. In parallel, the dissolved cligosiban significantly decreased the expression of cell-cycle-regulatory genes, including Cyclin-dependent kinase 1 and Cyclin E2 in the two mesothelioma cell lines with OXTR -high expression. In an orthotopic Y-MESO-27 model established by intrathoracic injection of mesothelioma cells with high- OXTR expression into nude mice, intrathoracic administration of the dissolved cligosiban at 50-400 µM was performed. Administration at 100 µM every other day clearly suppressed tumor growth and demonstrated a statistically significant prolongation of survival. Similar trends were observed in an intrathoracic MSTO-211H model, which is mesothelioma cells with low- OXTR expression. Next, we implanted the Alzet osmotic pump into the mice subcutaneous tissue and continuously administered total 400 μL (100 µM) of the dissolved cligosiban into the mice thoracic cavity. With injection rate at 1μl/hr, the dissolved cligosiban significantly prolonged mice survival. Conclusion Intrathoracic administration of the dissolved cligosiban effectively suppresses mesothelioma progression, representing the first demonstration of OXTR-targeted local therapy as a promising strategy for pleural mesothelioma.