Arsenic sulfide nanoformulation induces erythroid differentiation in chronic myeloid leukemia cells through degradation of BCR-ABL.

Abstract

BACKGROUND:

Chronic myeloid leukemia (CML) is a myeloproliferative disorder due to the existence of BCR-ABL fusion protein that allows the cells to keep proliferating uncontrollably. Although tyrosine kinase inhibitors can inhibit the activity of BCR-ABL fusion protein to trigger the cells apoptosis, drug resistance or intolerance exists in part of CML patients. Arsenic sulfide in its raw form (r-As4S4) can be orally administrated and certain therapeutic effects have been found out in the treatment of hematologic malignancies through inducing cell apoptosis.

METHODS:

In this work, a water-dissolvable arsenic sulfide nanoformualtion (ee-As4S4) composed of As4S4 particulates with 470 nm in diameter and encapsulated by a kind of hydrophilic polymer was fabricated and applied to the CML cell line K562, K562/AO2 and primary cells from the bone marrow of CML patients.

RESULTS:

Results showed that instead of inhibiting the activity of BCR-ABL, ee-As4S4 induced direct degradation of BCR-ABL in K562 cells within 6 hr incubation, followed by the occurrence of erythroid differentiation in K562 after 72 hr incubation, evidenced by the significantly upregulated CD235a and benzidine staining, which was not detectable with r-As4S4. The ee-As4S4-induced erythroid differentiation was also observed in K562/AO2 cells and bone marrow mononuclear cells of CML patients. Mechanistic studies indicated that ee-As4S4 induced autophagy by downregulating the level of intracellular ROS and hypoxia-inducible factor-1α significantly, which led to the subsequent degradation of BCR-ABL. When the concentration was increased, ee-As4S4 induced much more significant apoptosis and cell cycle arrest than r-As4S4, and the cytotoxicity of the former was about 178 times of the latter.

CONCLUSION:

ee-As4S4 was capable of inducing significant erythroid differentiation of CML cells by inducing the direct degradation of BCR-ABL; the new effect could improve hematopoietic function of CML patients as well as inhibit the leukemic cell proliferation.

• Authors: Tao Wang, Tao Wen, Hongmin Li, Bing Han, Suisui Hao, Chuan Wang, Qiang Ma, Jie Meng, Jian Liu, Haiyan Xu
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 14 Pg. 5581-5594 ( 2019) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 31413564 (Publication Type: Journal Article)

Chemical References

• Arsenicals
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• Sulfides
• arsenic trisulfide
• Fusion Proteins, bcr-abl
• p38 Mitogen-Activated Protein Kinases

Topics

• Apoptosis (drug effects)
• Arsenicals (pharmacology)
• Autophagy (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Down-Regulation (drug effects)
• Drug Compounding
• Erythroid Cells (cytology, drug effects, ultrastructure)
• Fusion Proteins, bcr-abl (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• MAP Kinase Signaling System (drug effects)
• Nanoparticles (chemistry)
• Phosphorylation (drug effects)
• Proteolysis (drug effects)
• Reactive Oxygen Species (metabolism)
• Sulfides (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)