Tumor hypoxia is a major mechanism of resistance to radiation therapy (RT), which is associated with poor prognosis in affected cancer patients. Various approaches to treat hypoxic and radioresistant cancers, including pancreatic cancer, have shown limited success. Fucoidan, a polysaccharide from brown seaweed, has antitumor and antiangiogenesis activities. Here, we discuss the development of fucoidan-coated manganese dioxide nanoparticles (Fuco-MnO2-NPs) and testing of the therapeutic potential with RT using pancreatic cancer models. In vitro data showed that Fuco-MnO2-NPs generated oxygen efficiently in the presence of H2O2 and substantially suppressed HIF-1 expression under a hypoxic condition in human pancreatic cancer cells. Fuco-MnO2-NPs reversed hypoxia-induced radioresistance by decreasing clonogenic survival and increasing DNA damage and apoptotic cell death in response to RT. In a BxPC3 xenograft mouse model, the combination treatment with Fuco-MnO2-NPs and RT resulted in a greater tumor growth delay than RT alone. Fucoidan-coated NPs, but not naked ones, further suppressed tumor angiogenesis, as judged by immunohistochemistry data with diminished expression of phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2) and CD31. These data suggest that Fuco-MnO2-NPs may potentiate the effects of RT via dual targeting of tumor hypoxia and angiogenesis, and they are of great clinical potential in the treatment of hypoxic, radioresistant pancreatic cancer.

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.