Biological responses to arsenic compounds

Abstract

Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As(2)O(3)), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As(2)O(3). Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.

FIGURE 1.

Key cellular events associated with induction of arsenic-dependent apoptosis.

FIGURE 2.

Proposed model for As₂O₃-dependent activation of the mTOR pathway in a negative feedback regulatory manner in malignant cells. PI3K, phosphatidylinositol 3-kinase; S6K, S6 kinase; 4E-BP, eukaryotic initiation factor 4E-binding protein; rpS6, ribosomal protein S6; eIF, eukaryotic initiation factor.