Mechanism of action of arsenic trioxide

My boss, on a half-minute pit-stop in the data-integration office, uttered concern about the liberal use of the term 'ancient remedy' in a recent Science paper [1] that reports the mechanism of action of As₂O₃ in the treatment of acute promyelocytic leukemia (APL).

His complaint dumbfounded me, so strong was my conviction that As₂O₃ is used, if at all, to kill off parasites or for the poisoning of competing heirs in the Medici family.
However, already in the the seventies, chinese scientists at Harbin University tested a solution they had reproduced from a traditional recipe, Ai-Ling No.1, in cancer patients and in subsequent studies found that it was an effective treatment for APL [2]. In APL, a chromosomal translocation leads to the formation of PML-RARα, a fusion protein that contains a retinoic acid receptor domain and that prevents myeloid differentiation. In the nineties, the active ingredient of Ai-Ling No.1 was determined to be As₂O₃ [3] and the substance is now used in combination with retinoic acid to treat APL, FDA aproved at that. But even earlier, in the 19th century, the As₂O₃-containing Fowler's solution was reported to have cured a patient from acute leukemia by the Breslau physician Heinrich Lissauer [4].
As reported recently, the mechanism of action of As₂O₃ has recently been unravelled, the As²⁺ cation replaces Zn²⁺ in the zinc-finger domain of the RARα part of PML-RARα and induces a conformational change that leads to oligomerisation of the fusion protein. The aggregated proteins are ubiquitinated and SUMO-modified, which leads to their rapid degradation, allowing the dysfunctional myeloid precursor cell to differentiate normally.

Whether As₂O₃ can legitimately be called an ancient remedy remains questionable, after all traditional medicines are generally applied to a a wide and often diffuse spectrum of symptoms while APL is a very specific and rare form of blood cancer.


References:
[1] Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de Thé H, Chen SJ, Chen Z: Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328(5975):240-3, 2010

[2] Zhang TD: Treatment of acute granulocytic leukemia with “Ai ling No. 1”: clinical analysis and experimental research. Chin J Comb Trad West Med 4:19-20, 1984

[3] Zhang P, Wang SY, Hu LH, et al: Treatment of acute promyelocytic leukemia with arsenic trioxide injection (“713”): Clinical observations and study of action mode. Chin J Hematol 17:58-60, 1996

[4] Lissauer, H: Zwei Fälle von Leucaemie. Berliner Klinische Wochenschrift, 2, 403–404, 1865