Dihydroartemisinin inhibits the Bcr/Abl oncogene at the mRNA level in chronic myeloid leukemia sensitive or resistant to imatinib.

Abstract

Due to the mutations of the Bcr/Abl oncogene that obstacle the binding of the protein with imatinib, the resistance to imatinib has developed in a significant portion of chronic myeloid leukemia (CML) patients. It stimulated the search for novel molecules for treatment of imatinib-resistance CML. Inhibiting the amplification of Bcr/Abl oncogene is believed to be a new effective strategy to override the imatinib resistance on CML cells. In present research, we demonstrated that dihydroartemisinin (DHA), a safe and effective antimalarial analog of artemisinin, could significantly inhibit the Bcr/Abl fusion gene at the mRNA level in CML cells sensitive or resistant to imatinib (including the primary CML cells with T315I mutation) and induce cell death. Moreover, dihydroartemisinin could also lead to the inhibition of the Bcr/Abl protein expression and tyrosine kinase activity, and strongly suppress on the downstream signals of Bcr/Abl, which included inhibition of tyrosine kinase activity of AKT and ERK, promotion of cytochrome c release from the mitochondria and the consequential activation of caspase-9/3 in imatinib-resistant CML cells. These results suggest for the first time that Dihydroartemisinin might be a potential novel drug candidate for treatment of imatinib-resistant CML and worthy of further study.

• Authors: Jun Lee, Peiqiang Shen, Guobing Zhang, Xiuhua Wu, Xingguo Zhang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 67 Issue 2 Pg. 157-63 (Mar 2013) ISSN: 1950-6007 [Electronic] France
• PMID: 23201011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antimalarials
• Artemisinins
• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Messenger
• artenimol
• Imatinib Mesylate
• Cytochromes c
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Caspase 9

Topics

• Antimalarials (pharmacology)
• Apoptosis (drug effects, genetics)
• Artemisinins (pharmacology)
• Benzamides (pharmacology)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Cytochromes c (genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Genes, abl (genetics)
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• MAP Kinase Signaling System (drug effects, genetics)
• Mitochondria (drug effects, genetics, metabolism)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics)