ABSTRACT

Functions .................................................................................................. 111 6.3 Selenite: A Potent Chemotherapeutic Agent ................................................ 112

6.3.1 In Vitro Studies ................................................................................. 112 6.3.2 In Vivo Studies with Animal Models ............................................... 113

6.4 The Molecular Basis of Selenite Cytotoxicity in Cancer ............................. 115 6.4.1 Selenite Transport in Cancer Cells ................................................... 115 6.4.2 Generation of Reactive Oxygen Species ........................................... 117 6.4.3 Modulation of Important Cancer-Associated Signaling Pathways

by Selenite ......................................................................................... 118 6.4.3.1 Translational Machinery .................................................... 118 6.4.3.2 Cell Cycle ........................................................................... 119 6.4.3.3 p53 ...................................................................................... 119 6.4.3.4 HIF-1α ................................................................................ 120 6.4.3.5 NF-κB ................................................................................ 120 6.4.3.6 AP-1 ................................................................................... 121 6.4.3.7 Epigenetic Signature .......................................................... 121

6.4.4 Possible Mechanisms and Evidence for Potentiation of Cytotoxic Effects of Selenite with Chemotherapeutic Drugs ...... 123

6.5 Human Studies ..............................................................................................124 6.5.1 Rationale for Use of Selenium in Treatment of Cancer Patients ......124 6.5.2 Selenium in Combination with Surgery, Radiotherapy,

and Chemotherapy ............................................................................ 125 6.5.3 Use of Selenium as a Chemotherapeutic Drug in Humans .............. 125 6.5.4 Phase I Study to Assess Safety and to Determine the Maximal

Tolerable Dose .................................................................................. 129 6.6 Concluding Remarks .................................................................................... 129 Acknowledgments .................................................................................................. 130 References .............................................................................................................. 130

Almost a century ago, the highly unique properties of selenium to inhibit the growth of neoplastic cells and the great potential of selenium in the treatment of neoplasia were described (Watson-Williams, 1919). Nearly 40 years later, selenocystine was shown to be efficient in the treatment of leukemia (Weisberger and Suhrland, 1956). In spite of these positive indications, the number of human trials using selenium compounds in the treatment of malignancies is very limited. The reasons for this fact are difficult to understand, but one possible explanation is the simplicity of the compounds and of the concept of using a single element and simple naturally occurring molecules of this element. At the end of the 1940s, modern oncology developed rapidly, and a number of cytostatic substances emerged from chemical weapons from World War II, including nitrogen-mustard gas derivatives. It is possible that the focus on these substances caused the concept of selenium as a cytostatic drug to be forgotten. However, numerous in vitro and animal studies have provided further and solid proof of the cytotoxic potential of redox-active selenium compounds during the past decades. There are two distinct pathways of selenium focused cancer research, that is, prevention and treatment, between which the dominating path has been prevention. These two lines of research are often mixed, leading to confusion, which is not beneficial for the field. Selenium in the prevention of cancer follows completely different mechanisms compared to selenium as a therapeutic agent (Steinbrenner et al., 2013). In the former role, the antioxidant properties are crucial as are the connection to selenoproteins. The field of selenoproteins has dominated selenium research for decades. However, selenoproteins that are the base for the physiological, antioxidant, and preventive effects of selenium are likely of minor importance in the antiproliferative and cytotoxic effects of selenium, that is, in the role of selenium as a cytostatic drug. Selenite is the most widely studied selenium compound. Due to the high reactivity and first passage effect in the liver, the compound requires intravenous administration to achieve a fast increase in redox-active selenium species in the blood. There are numerous reports on the antiproliferative effects of selenium in vitro, and in these laboratory investigations, mostly selenite has been applied, and recently a new class of methylated selenium compounds is used in various tumor models and cell lines with striking results. However, in the few human cancer trials that have been published, redox-active selenium compounds or precursors of redox-active selenium compounds, that is, selenite and methylated species, for which there are an abundance of positive data, have not been used. Instead, the relatively inert SeMet has been applied. Furthermore, vitamin E has, for some reason, been combined in high amounts of selenium, demonstrating the common misinterpretation of antioxidant to pro-oxidant effects. This chapter will summarize the current knowledge of the therapeutic potential of selenite. A major aim is to clarify mechanisms and the differences in preventive and chemotherapeutic effects and to emphasize the importance of using redox-active selenium compounds in cancer therapeutics.