The Redox-Active Manganese(III) Porphyrin, MnTnBuOE-2-PyP(5+), Impairs the Migration and Invasion of Non-Small Cell Lung Cancer Cells, Either Alone or Combined with Cisplatin

SIMPLE SUMMARY: Oxidative stress affects several features of cancer, including those related to metastases formation. Non-small cell lung cancer (NSCLC) is commonly detected in advanced stages when metastases have already developed. MnTnBuOE-2-PyP(5+) (MnBuOE, BMX-001) is a redox-active Mn porphyrin-based drug, and a mimic of superoxide dismutase, that is currently in clinical trials for several types of cancer. Nevertheless, there is still insufficient information regarding the effect of this compound on lung cancer. Here, we aim at filling this gap by assessing the impact of MnBuOE alone or combined with cisplatin—a frequently used platinum-based drug in chemotherapy—on the viability and migration of two NSCLC cell lines. Although MnBuOE only displayed moderate effects on suppressing cancer cell viability, it significantly reduced collective and individual migration and invasion in both types of cells, especially when combined with cisplatin. The data thus support the therapeutic potential of MnBuOE as an anti-metastatic drug for the treatment of NSCLC. ABSTRACT: Manganese(III) porphyrin MnTnBuOE-2-PyP(5+) (MnBuOE, BMX-001) is a third-generation redox-active cationic substituted pyridylporphyrin-based drug with a good safety/toxicity profile that has been studied in several types of cancer. It is currently in four phase I/II clinical trials on patients suffering from glioma, head and neck cancer, anal squamous cell carcinoma and multiple brain metastases. There is yet an insufficient understanding of the impact of MnBuOE on lung cancer. Therefore, this study aims to fill this gap by demonstrating the effects of MnBuOE on non-small cell lung cancer (NSCLC) A549 and H1975 cell lines. The cytotoxicity of MnBuOE alone or combined with cisplatin was evaluated by crystal violet (CV) and/or 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-Tetrazolium (MTS) reduction assays. Intracellular ROS levels were assessed using two fluorescent probes. Furthermore, the impact of MnBuOE alone or in combination with cisplatin on collective cell migration, individual chemotactic migration and chemoinvasion was assessed using the wound-healing and transwell assays. The expression of genes related to migration and invasion was assessed through RT-qPCR. While MnBuOE alone decreased H1975 cell viability at high concentrations, when combined with cisplatin it markedly reduced the viability of the more invasive H1975 cell line but not of A549 cell line. However, MnBuOE alone significantly decreased the migration of both cell lines. The anti-migratory effect was more pronounced when MnBuOE was combined with cisplatin. Finally, MnBuOE alone or combined with cisplatin significantly reduced cell invasion. MnBuOE alone or combined with cisplatin downregulated MMP2, MMP9, VIM, EGFR and VEGFA and upregulated CDH1 in both cell lines. Overall, our data demonstrate the anti-metastatic potential of MnBuOE for the treatment of NSCLC.