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Assessment of the Metabolic Profile of Primary Leukemia Cells
Published on: November 21, 2018
A modified DAW-22 compound F-B1 inhibits Bcr/Abl and induces apoptosis in chronic myelogenous leukemia cells
Fengling Wang1, Jinhui Wang2, Zhaozhong Chong3
1Key laboratory for Rare Disease of Shandong Province, Department of Pharmacology, Institute of Materia Medica, Shandong Academy of Medical Sciences, Jinan.
Abstract:
The Bcr/Abl kinase is an oncogenic fusion protein that plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Some small-molecule kinase inhibitors such as imatinib were developed in the treatment of CML; however, resistant to imatinib is an emerging problem of CML therapy. Hence, additional approaches or compounds targeting leukemogenic cells are required. F-B1 is a new compound obtained by modifying DAW-22, a natural sesquiterpenoid coumarin, which was isolated from traditional Chinese medicine Ferula ferulaeoides (Steud.) Korov. F-B1 was found to inhibit the growth of myelogenous leukemia cell lines, that is, K562 cells bearing wild-type Bcr/Abl and imatinib-resistant K562G cells. F-B1 potently down-regulated the mRNA and protein levels of Bcr/Abl, followed by suppression of the downstream molecules such as Akt, externally regulated kinases, and nuclear factor κB. In addition, F-B1 also induced cell apoptosis by impairing the balance between proapoptotic protein Bax and antiapoptotic proteins Bcl-2 and Bcl-XL and increased the activity of mitochondrial-dependent apoptosis in nude mouse xenografts. Experimental validation results together demonstrated that F-B1 can inhibit Bcr/Abl fusion proteins in K562 and K562G cells, implying that F-B1 might be a promising drug to treat CML, especially the imatinib-resistant CML.
Insights
A novel compound, F-B1, effectively inhibits the Bcr/Abl fusion protein in chronic myeloid leukemia (CML) cells, including imatinib-resistant strains. This suggests F-B1 is a potential new therapy for CML, particularly resistant forms.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The Bcr/Abl fusion protein drives chronic myeloid leukemia (CML).
- Imatinib resistance is a significant challenge in CML treatment.
- Novel therapeutic agents targeting CML are urgently needed.
Purpose of the Study:
- To evaluate the efficacy of F-B1, a novel sesquiterpenoid coumarin derivative, against CML cells.
- To investigate the molecular mechanisms underlying F-B1's anti-leukemic activity.
- To assess F-B1's potential in treating imatinib-resistant CML.
Main Methods:
- In vitro studies using K562 (wild-type Bcr/Abl) and K562G (imatinib-resistant) cell lines.
- Analysis of Bcr/Abl, Akt, ERK, and NF-κB expression at mRNA and protein levels.
- Assessment of apoptosis induction, including mitochondrial pathways and Bcl-2 family proteins.
- In vivo efficacy evaluation in nude mouse xenograft models.
Main Results:
- F-B1 inhibited the proliferation of both wild-type and imatinib-resistant CML cell lines.
- F-B1 significantly down-regulated Bcr/Abl expression and its downstream signaling pathways.
- F-B1 induced apoptosis by modulating Bax/Bcl-2/Bcl-XL balance and activating mitochondrial pathways.
- F-B1 demonstrated anti-leukemic activity in vivo.
Conclusions:
- F-B1 effectively targets Bcr/Abl fusion proteins in CML cells.
- F-B1 exhibits potent anti-leukemic and pro-apoptotic effects.
- F-B1 represents a promising therapeutic candidate for CML, including imatinib-resistant cases.
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