The evolving use of arsenic in pharmacotherapy of malignant disease

Abstract

For more than 2,000 years, arsenic and its derivatives have shown medical utility. Owing to the toxicities and potential carcinogenicity of arsenicals, their popularity has fluctuated. The exact mechanism of action of therapeutic arsenic is not well characterized but likely to involve apoptosis, generation of reactive oxygen species, inhibition of intracellular transduction pathways, and cell functions. Arsenic trioxide has received approval for use in patients with relapsed acute promyelocytic leukemia for remission induction. Arsenic has additionally shown activity in a range of solid tumors, myelodysplastic syndrome, multiple myeloma, and in autoimmune diseases. The following is a review of the history of arsenic, its cellular metabolism, pharmacology, genetic basis of disposition, associated toxicities, and clinical efficacy.

A Novel Pathway for Arsenic Elimination: Human Multidrug Resistance Protein 4 (MRP4/ABCC4) Mediates Cellular Export of Dimethylarsinic Acid (DMAV) and the Diglutathione Conjugate of Monomethylarsonous Acid (MMAIII)

“…Pharmacokinetic studies of patients undergoing chemotherapy for acute promyelocytic leukemia with As 2 O 3 have plasma levels in the low-micromolar range (Yoshino et al, 2009). Environmental exposure would be approximately 100-fold lower, with expected tissue levels in the 100 nM range (Kritharis et al, 2013).…”

“…Thus, arsenic is a major worldwide public health issue. In addition to environmental exposures, arsenic trioxide (As 2 O 3 ) has been approved for treating both newly diagnosed and relapsed acute promyelocytic leukemia, and is under investigation for the treatment of multiple other hematologic and solid tumors (Kritharis et al, 2013).…”

Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl‐2/Bax pathway

“…(J Occup Health 2015; 57: 212-221) Key words: Apoptosis, Arsenic trioxide, Bax, Bcl-2, Hippocampus, Neurotoxicity Arsenic (As), a naturally occurring toxic metalloid found in both inorganic and organic forms, is ubiquitous in the environment and contaminates water as a result of geological and industrial pollution 1) . Moreover, some kinds of arsenide, such as arsenic trioxide (As 2 O 3 ), are also widely used for the treatment of malignant tumors 2) . In As-contaminated areas, the As concentration in drinking water or groundwater ranges from 0.25 to 2.1 ppm and even reaches >3.0 ppm in some severely contaminated areas 3−5) .…”

“…Moreover, some kinds of arsenide, such as arsenic trioxide (As 2 O 3 ), are also widely used for the treatment of malignant tumors 2) . In As-contaminated areas, the As concentration in drinking water or groundwater ranges from 0.25 to 2.1 ppm and even reaches >3.0 ppm in some severely contaminated areas 3−5) .…”

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

“…In addition to cancer, arsenic exposure is associated with other adverse health effects, such as diabetes and hypertension (Platanias, 2009). Somewhat paradoxically, arsenic trioxide (As 2 O 3 ) is highly effective in the treatment of acute promyelocytic leukemia and more recently is in clinical trials as a therapy for other hematologic and solid tumors (Kritharis et al, 2013).…”