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Submitted to: Biological Trace Element Research
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 2/10/2001 Publication Date: 10/1/2001 Citation: Zeng, H. 2001. Arsenic suppresses necrosis induced by selenite in human leukemia HL-60 cells. Biological Trace Element Research. 83:1-15. Interpretive Summary: Programmed cell death is a highly regulated physiological process. Alterations in cell death have been implicated in many human diseases, including cancer and AIDS. Two mineral elements, selenium and arsenic, may play key roles in affecting cell death. Selenium, an essential trace element, has anti-cancer effects when it is given in amounts that exceed the nutritional requirement. Arsenic, an element whose essentiality has not been demonstrated in humans, has been used as an effective treatment for leukemia. The anti-cancer effects of selenium and arsenic have been related to their ability to stimulate programmed cell death. Because humans consume multiple elements simultaneously, it is important to learn how they may interact to protect against disease at the level of the cell. In studies of cells in culture, arsenic, but not selenium, enhanced the binding of a specific activator protein to DNA of cancer-prone cells and thus promotes cell death. Also, high doses of selenium induce death of cancer-prone cells, and this cell death may be inhibited with arsenic. These findings suggest that the cell death induced by high doses of selenium may be neutralized by arsenic at the cellular level. In practical terms, the recommendation for daily requirement for selenium should take into consideration intake of arsenic or other selenium- antagonistic dietary components to decrease the risk of cancer development. This information will be useful to scientists who seek to define mineral element requirements to promote health. Technical Abstract: Selenium, as an essential mineral trace element for human nutrition, has been shown to have anti-cancer effects at doses higher than that of the nutritional requirement. Arsenic, as another trace element, has been shown to be effective in treatment of leukemia. Anti-cancer effects of selenium and arsenic have been related to their ability to induce apoptosis. Because humans are exposed to diverse trace elements simultaneously, it is important to learn biological effects of their interactions at a cellular level. We first demonstrate that sodium selenite (Na2SeO3) causes apoptosis at around 3 u and necrosis at high concentrations (> 3 uM) in HL-60 cells. Similarly, both sodium arsenite (NaAsO2) at 50 uM and sodium arsenate (Na2HAsO4) at 500 uM induce apoptosis,but at higher concentration (>50 uM, >500 uM respectively) they induce necrosis in HL-60 cells. Arsenic, but not selenium, enhances AP-1 DNA-binding activity, indicating different mechanisms for apoptosis induced by these two elements. Interestingly, we observed that HL-60 cell necrosis induced by high concentration of selenium is essentially inhibited by arsenic, resulting in a net effect of apoptosis. Because AP-1 DNA binding activity is not induced in the presence of a combination of necrotic level of selenium and apoptotic level of arsenic, the observed apoptosis apparently is through the mechanism used by selenium. These results suggest for the first time that necrotic effect of selenium could be neutralized by arsenic at the cellular level. |
