Kinase Regulation by Sulfur and Selenium Containing Compounds

Abstract

Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.

Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer

“…Nevertheless, although inorganic Se has been shown to inhibit carcinogenesis, there is a concern about toxicity, since chronic feeding of inorganic Se (e.g., selenites or selenates) at levels of> 5 ppm is toxic in rodents. However, on the basis of the pioneering work of El-Bayoumy et al [ 14 – 16 ] and Sanmartin et al [ 17 – 19 ], a series of synthetic Se compounds have been elaborated, in which the Se atom is connected to two carbon atoms, as in complex 1 . These compounds have proved notably more potent and much less toxic than the inorganic counterparts.…”

Sulphurous Mineral Waters: New Applications for Health

“…This is done through the two genes mitogen-activated protein- (MAP-) kinase-1, an ERK gene (extracellular signal-regulated kinase), and p38, a gene with effects on chaperone heat shock protein 27 (Hsp27) that promotes VEGF secretion. In turn, VEGF inhibits apoptosis, regulating cell development, differentiation, and cell function [40]. …”

Biological responses related to agonistic, antagonistic and synergistic interactions of chemical species

“…In humans, studies suggest that replacing sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs [166].…”