Selenium-containing Compounds Sensitize Chemotherapeutic Drugs And Radioactive Seeds To Inhibit Cancer Cells Growth And Metastasis

Nowadays the malignant tumorspose a serious threat to human body health, and chemotherapy is an important means for the treatment of malignant tumor. But in recent years, the side effects of chemotherapy drugs and the emergence of drug resistance phenomenon hindered the development in the clinical application. Therefore, the development of new chemotherapy drugs and sensitization agent to improve the sensitivity of tumor cells to chemotherapy drugs or new drug strategies is urgently needed. And selenium, one of the essential microelements, has extensive biological functions, playing an important role in the metabolism of human body in various ways. In recent years, studies have shown that Selenium-containing compounds in the treatment of malignant tumor have been the important role andverified by a large number of epidemiology and clinical research results. Among them, some compounds which have good antitumor activity, could also be able to together a variety of clinical chemotherapy drugs to improve its sensitivity to the tumorand reduce the occurrence of drug resistance phenomenon. So based onthe characteristics ofthe risk-benefit ratio and high bioavailability, the development of selenium-containing compoundshas become a hot spot. This first paper discussed the anti-tumor effect and mechanism of action ofthe seven organic selenium drugs, and tested thatthe representative compounds impacted onthe transfer of cancer cells. At the same time, according to the unique synergistic sensitization ofthe organic selenium, combining selenium compounds and metal ions to form selenium（Se）-containing Fe complexes（Fe Se）, we not only tested its antitumor activityin vitro and in vivo, and the molecular mechanismof synergy sensitization antitumor effect of chemotherapy drugs（TRAIL） wasdeeply expounded through the analysis of structure-activity relationship.Finally, we studied the in vitro antitumor activity and the mechanism action of nanoselenium（GP-Se NPs） combined with ¹²⁵I radioactive seeds. The specific research results are as follows:1. In the present study, a series of selenadiazole derivatives（Se Ds） have been rationally designed, synthesized and found be able to actively suppress the growth and metastasis of bladder cancer cells. The Se Ds demonstrated better antiproliferative activity and higher stability under different physiological conditions, especially in acidic urocystic environment, than mitomycin, a clinically used anti-bladder cancer drug. Particularly, compounds exhibited better selectivity between cancer and normal cells in comparison with other compounds. The studies on the structure-activity relationship revealed that, the introduction of strong electron donating substituent, such as the methoxy group, resulted in dramatic enhancement in the anticancer efficacy. Furthermore, Se Ds induced anti-migration and anti-invasion activity of bladder cancer cells. Mechanistic investigation revealed that Se Ds was able to enter the cells through endocytosis, and then trigger reactive oxygen species（ROS） overproduction, further induce DNA damage-mediated p53 phosphorylation and promote cancer cell apoptosis through the regulation of AKT and MAPKs signaling pathways. Altogether, this study provides a strategy for rational design of selenadiazole derivatives with improved stability to antagonize bladder cancer.2. This chapter studied theantitumor activity of selenium（Se）-containing Fe complexes（Fe Se）associated with chemotherapy drugs TRAIL, through the analysis of structure-activity relationship and molecular mechanisms of anticancer in the cell and animal levels. Results showed that Fe Se not only had better antitumor activity, but also could better inhibittumor spheres（MCTSs） and had good ability to penetrate tumor spheres, what else could better inhibitthe transfer oftumor cells. And mechanism study showed that better synergy increased TRAIL inducing tumor cells apoptosis through mediatedthe intracellular accumulationof ROS to regulate MAPKs, the activity of AKT, and DNA damage mediated p53 phosphorylation.3.This chapter explored theanticancer activity of GP-Se NPscombined with ¹²⁵I radioactive seedsin vitro. Results showed that the nanoselenium GP-Se NPs joined¹²⁵I radioactive seedsinhibited the cancer cells growth by inducing apoptosis and G2/M phase retardation. Molecular mechanism and further studies have shown that functional GP-Se NPs united ¹²⁵I radioactive seedslead to cell apoptosisby causing the accumulation of intracellular reactive oxygen species to activate caspase family proteins and induce DNA damage.To sum up, this paper integrated a variety of biological methods toresearchthe antitumor activity of different forms of selenium, and exhibited new strategies to improve its antitumor effect and further expounded the mechanism action. The results indicate the potential application value of selenium in chemotherapy. This study not only broadens the design strategy of new drugs, also discussesthe novel strategy for drug combinations, further get into the study of selenium to provide scientific basis for clinical therapy.