Fe-SOD cooperates with Nutlin3 to selectively inhibit cancer cells in vitro and in vivo

• Published in: Biochemical and biophysical research communications Vol. 431; no. 2; pp. 169 - 175
• Main Authors: Qin, Yong, Dai, Wei, Wang, Yu, Gong, Xing-Guo, Lu, Min
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2013
• Subjects: agonists; Animals; Cancer targeting; cell growth; Cell Proliferation - drug effects; clinical trials; Cyclin-Dependent Kinase Inhibitor p27 - biosynthesis; Drug Synergism; drugs; Fe-SOD; Female; Hep G2 Cells; homeostasis; Humans; Imidazoles - administration & dosage; Liposomes; MCF-7 Cells; Melanoma, Experimental - drug therapy; Mice; neoplasm cells; Neoplasms - drug therapy; Nutlin3; Piperazines - administration & dosage; reactive oxygen species; Reactive Oxygen Species - metabolism; ROS; Skin Neoplasms - drug therapy; Superoxide Dismutase - administration & dosage; Synergistic inhibition; tissues; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; Fe-SOD; Synergistic inhibition; Nutlin3; Cancer targeting; ROS
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2013.01.001

► Fe-SOD selectively targeted cancer cells independent of p53 status. ► Co-treatment of Fe-SOD and Nutlin3 showed synergistic inhibition on cancer cells in vitro. ► p27 was synergistically induced by Fe-SOD and p53. ► Co-treatment of Fe-SOD and Nutlin3 further exhibited synergistic inhibition on tumor growth in vivo. Nutlin3, a non-genotoxic agonist of p53, is currently in phase II clinical trials for cancer treatment. However, its effects on normal tissues and cell types remain largely to be determined. Drugs that can selectively target cancer cells as well as cooperate with the p53 pathway are thus greatly needed. Iron-superoxide dismutase (Fe-SOD) is a potential candidate as it selectively targets cancer cells by eliminating the abnormally high levels of reactive oxygen species (ROS) in cancer cells; it also inhibits cancer cell growth by induction of p27. Here, we show evidence that modulating redox and ROS homeostasis cooperates with Nutlin3 to selectively inhibit cancer cells in vitro and in vivo. Co-treatment of Fe-SOD and Nutlin3 showed synergistic inhibition on cancer cells in vitro, and the induction of p27 appeared to be involved. No effects were observed on normal cells. In addition, such co-treatment further exhibited synergistic inhibition on tumor growth in vivo in a murine B16 xenograft model, while the individual treatments only achieved very limited inhibition. Thus, Fe-SOD cooperated with Nutlin3 to selectively inhibit cancer cells in vitro and in vivo.