MnTnHex-2-PyP5+, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways

Abstract

Tumor migration and invasion induced by the epithelial-to-mesenchymal transition (EMT) are prerequisites for metastasis. Here, we investigated the inhibitory effect of a mimic of superoxide dismutase (SOD), cationic Mn(III) ortho-substituted N-n-hexylpyridylporphyrin (MnTnHex-2-PyP5+, MnHex) on the metastasis of breast cancer in cellular and animal models, focusing on the migration of tumor cells and the factors that modulate this behavior. Wound healing and Transwell migration assays revealed that the migration of mouse mammary carcinoma 4T1 cells was markedly reduced during the concurrent treatment of MnHex and radiation therapy (RT) compared with that of the control and RT alone. Bioluminescence imaging showed that MnHex/RT co-treatment dramatically reduced lung metastasis of 4T1 cells in mice, compared with the sham control and both single treatments. Western blotting and immunofluorescence showed that MnHex treatment of 4T1 cells reversed the RT-induced EMT via inhibiting AKT/GSK-3β/Snail pathway in vitro, thereby decreasing cell migration and invasion. Consistently, histopathological analyses of 4T1 tumors showed that MnHex/RT reduced Snail expression, blocked EMT, and in turn suppressed metastases. Again, in the human metastatic breast cancer MDA-MB-231 cell line, MnHex inhibited metastatic potential in vitro and in vivo and suppressed the RT-induced Snail expression. In addition to our previous studies showing tumor growth inhibition, this study demonstrated that MnHex carries the ability to minimize the metastatic potential of RT-treated cancers, thus overcoming their radioresistance.

MnTnHex-2-PyP5+ Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells

“…When MnTnHex was combined with radiotherapy, it significantly reduced the migration and invasion of mouse mammary carcinoma 4T1 cells compared to control and radiation therapy alone. Similar to the results obtained in this work, MnTnHex as a single drug was the best in reducing migration [ 30 ].…”

“…This redox-active compound is the most lipophilic MnP, having high bioavailability and distribution while at the same time displaying low toxicity in healthy cells and tissues [ 25 ]. MnTnHex has been studied in different types of cancer, e.g., breast, renal cancer, and glioblastoma [ 24 , 29 , 30 , 31 ]. It was also found to reduce the viability and migration of renal metastatic cancer cells [ 29 ].…”

Cellular Localization of Selected Porphyrins and Their Effect on the In Vitro Motility of Human Colon Tumors and Normal Cells

“…Similar observations were made by Chen et al, indicating a decrease in the MMP-2 and MMP-9 expression in osteosarcoma MG 63 cells subjected to a MPPa-PDT treatment [ 46 ]. Another study showed that manganese porphyrin (MnTE-2-PyP 5+ ) significantly reduced the expression of mesenchymal markers but maintained an epithelial marker expression [ 47 ]. In turn, TMPyP4, a porphyrins derivative, is a quadruplex-specific ligand.…”

Emerging Trends in Metal‐based Anticancer Agents: Drug Design to Clinical Trials and their Mechanism of Action

“…Various cellular functions are changed as a result of MnTE-2-PyP 5 + and prooxidative capabilities, including suppression AP-1 and NF-kB activity and decreased expression of HIF1-α, VEGF, and TGFβ. [108,109] Furthermore, in certain cases, injecting malignant cells with a mixture of MnTE-2-PyP 5 + plus cyclophosphamide, doxorubicin or glucocorticoids made the cells more sensitive to these agents. [110] In addition to MnTE-2-PyP5 + , the combination of chemotherapy, radiation therapy, and immune-stimulating interleukin-2 therapy was also tested with the macrocyclic Mn(II) polyamine M40403.…”