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Research: CHEN and COLLEAGUES,
Listed in Issue 207
Abstract
CHEN and COLLEAGUES, Shanghai Institute of Hematology and State Key Laboratory for Medical Genomics, Rui Jin Hospital/Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai, China review, at the molecular level, the use of arsenic to treat and achieve complete remission and 90% 5-year overall survival in patients with acute promyelocytic leukemia.
Background
Arsenic had been used in treating malignancies from the 18th to mid-20th century.
Methodology
In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion.
Results
Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signalling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARalpha, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation / ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARalpha for degradation through its RARalpha moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits.
Conclusion
The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine.
References
Chen SJ, Zhou GB, Zhang XW, Mao JH, de The H and Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Source Blood. 117(24):6425-37. Jun 16 2011.
Comment
The above research update was a revelation to me, as I had no prior knowledge that arsenic has been used historically in cancer treatment nor that it can be combined for such excellent results in leukemia treatment and survival.
