Arsenic Sulfide Nanoformulation and CML Cells
Posted: Thursday, August 29, 2019
For patients diagnosed with chronic myeloid leukemia (CML) who have demonstrated a resistance to tyrosine kinase inhibitors (TKIs), research findings presented in the International Journal of Nanomedicine indicate that the arsenic sulfide nanoformulation ee-As4S4 may induce erythroid differentiation of CML cells by inducing the direct degradation of BCR-ABL fusion protein. According to Tao Wen, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, and colleagues, this approach may improve hematopoietic function in patients with CML and inhibit the proliferation of leukemic cells.
“Additionally, these results are of implications to treatments of other hematopoietic disorders caused by myeloid diseases,” the authors observed. “As4S4 showed anti-CML effect through degradation of BCR-ABL oncoprotein in K562 cells,” suggesting it may have curative potential as in CML.
In this study, the investigators fabricated a water-dissolvable arsenic ee-As4S4 composed of raw form arsenic sulfide—r-As4S4—and encapsulated by a hydrophilic polymer. That combination was then applied to CML cell line K562, K562/AO2, and primary cells from the bone marrow of patients with CML.
The authors found that instead of inhibiting BCR-ABL activity, ee-As4S4 inducted direct degradation of the fusion protein in K562 after 72 hours of incubation. The erythroid differentiation was also exhibited in K562/AO2 cells and bone marrow mononuclear cells. Mechanistic studies revealed that ee-As4S4 inducted autophagy by significantly downregulating the level of intracellular reactive oxygen species and hypoxia-inducible factor-1α, which consequently led to the degradation of the BCR-ABL protein.
Additionally, when authors increased the concentration, ee-As4S4 generated “much more significant apoptosis” and cell-cycle arrest than r-As4S4, with the cytoxicity of ee-As4S4 about 178 times that of the raw form of arsenic sulfide.
Disclosure: The study authors reported no conflicts of interest.