Growth inhibitory effect of dihydroartemisinin on Bcr/Abl+ chronic myeloid leukemia K562 cells involve AKT, ERK and NF-κB modulation.

Abstract

PURPOSE:

In our previous publication, we have shown that dihydroartemisinin could significantly inhibit the growth of CML K562 cells by its anti-proliferative and inducing apoptotic effects. Given the pivotal effect of Bcr/Abl tyrosine kinase and its downstream signal factors on CML cell proliferation and survival, we extend our study to investigate the effect of DHA on Bcr/Abl and related signal factors to further illuminate the possible mechanisms of the effect of DHA on CML cells.

METHODS:

The expression of Bcr/Abl was analyzed with PCR and Western blotting methods at both mRNA and protein levels. Measurement of protein expression and tyrosine phosphorylation activity of Bcr/Abl, AKT, ERK1/2, NF-κB and cytochrome c were performed with Western blotting and immunoprecipitation methods. Using the activity kits analyzed the activity of caspase 9 and caspase 3.

RESULTS:

The treatment with DHA results in a significant suppression on Bcr/Abl expression and leads to a concentration-dependent reduction on the Bcr/Abl tyrosine activity. Moreover, it also results in a strong influence on the downstream signal factors of Bcr/Abl, which includes inhibition of tyrosine kinase activity of AKT and ERK1/2, suppression of NF-κB protein expression, promotion of the cytochrome c release and the consequential activation of caspase 3/9 in CML K562 cells.

CONCLUSIONS:

Together with our previous report, our data show that the growth inhibitory effect of DHA on CML cells might be due to the influence on Bcr/Abl expression and its downstream signal factors. DHA might be a potential novel anti-CML drug candidate and worthy of further study.

• Authors: Jun Lee, Guobing Zhang, Xiuhua Wu, Feilong Xu, Jun Zhou, Xingguo Zhang
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 138 Issue 12 Pg. 2095-102 (Dec 2012) ISSN: 1432-1335 [Electronic] Germany
• PMID: 22833150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Artemisinins
• Growth Inhibitors
• NF-kappa B
• RNA, Messenger
• artenimol
• Cytochromes c
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Caspase 9

Topics

• Artemisinins (pharmacology)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochromes c (genetics, metabolism)
• Down-Regulation (drug effects)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Growth Inhibitors (pharmacology)
• Humans
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, genetics, metabolism)
• MAP Kinase Signaling System (drug effects, genetics)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Phosphorylation (drug effects, genetics)
• Protein-Tyrosine Kinases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics)