15 years of research on arsenic-induced health effects

抄録

Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the exact mechanism was unknown 15 years ago. Treatment with inorganic arsenite (As^III) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium and increased vasoconstrictions induced by several agonists mediated through calcium-sensitization in smooth muscles. In vivo studies revealed that intravenous administration of arsenite altered the blood pressure by agonists in conscious rats. In addition, arsenite induced in vitro aggregation when platelets were exposed to sub-threshold challenge by several agonists. Moreover, arsenite significantly enhanced procoagulant activity of human platelets as well. Consistent with the in vitro studies, 4-week ingestion of arsenite-contaminated drinking water resulted in enhanced arterial thrombosis. All these results provided new insights into the mechanisms of arsenic-induced cardiovascular disease. Until now, mechanism remains elusive for arsenic-associated cancer. Very recently, we demonstrated that arsenic promotes tumor metastasis through activating platelets and thereby, stimulating tumor cell-induced platelet aggregation (TCPA), a central contributor to immune-evasion and extravasation of tumor. In human platelets, arsenite promoted TCPA induced by cancer cells that include melanoma, lung carcinoma and sarcoma. Consistently, arsenite enhanced tumor cell extravasation; namely, the adhesion of tumor cells to vascular endothelial cells and extracellular matrix, and invasion in vitro. Importantly, subchronic ingestion of drinking water contaminated with arsenic lead to increased tumor metastasis in mouse. Of a particular note, arsenite-promoted metastasis was abolished by blockers of platelet activation like aspirin, demonstrating that anti-platelet agents may be effective for preventing arsenic-associated cancer death.