Arsenic compounds: revived ancient remedies in the fight against human malignancies

Arsenic, the 20th most abundant element in the earth crust, is one of the oldest drugs in the world. It was used in the 18th century in treating hematopoietic malignancies, discarded in 1950s in favor of chemotherapeutic agents (busulphan and others), and was revived in the 1970s due to its dramatic efficacy on acute promyelocytic leukemia (APL) driven by the t(15;17) translocation-generated PML-RARα fusion. Arsenic represents the most potent single agent for APL, and achieves a five-year overall survival of 90% in APL patients when combined with all-trans retinoic acid (ATRA) and chemotherapy (daunorubicin and cytarabine), turning this disease from highly fatal to highly curable. Arsenic triggers sumoylation/ubiquitination and proteasomal degradation of PML-RARα via directly binding to the C3HC4 zinc finger motif in the RBCC domain of the PML moiety and induction of its homodimerization/multimerization and interaction with the SUMO E2 conjugase Ubc9. Because of its multiplicity of targets and complex mechanisms of action, arsenic is widely tested in combination with other agents in a variety of malignancies. Other arsenic containing recipes including oral formulations and organic arsenicals are being developed and tested, and progress in these areas will definitely expand the use of arsenicals in other malignant diseases.