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Antibiotic anisomycin selectively targets leukemia cell lines and patient samples through suppressing Wnt/β-catenin
Yong Li1, Jialin Hu2, Hongping Song1
1Department of Pharmacy, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract:
Chronic myeloid leukemia (CML) responds well to BCR-ABL tyrosine kinase inhibitors (TKI), such as imatinib and dasatinib. However, these inhibitors have been less effective as single agents in the blast phase-CML. In this work, we show that anisomycin, a clinically available drug, targets CML cells at all stages of development and enhances BCR-ABL TKIs' efficacy. Anisomycin at nanomolar concentration inhibits proliferation and induces apoptosis in a panel of CML cell lines in a dose-dependent manner. It induces apoptosis CD34 stem/progenitor cells isolated from patients with blast phase CML. Using colony formation and serial replating assays, we further show that anisomycin inhibits CML CD34 cell differentiation, proliferation and self-renewal. Additionally, anisomycin is less effective in normal bone marrow (NBM) CD34 cells, suggesting the selective anti-leukemia activity of anisomycin. Combination of anisomycin with imatinib or dasatinib achieves significantly better efficacy than TKI alone in leukemia cell lines and patient samples while sparing normal counterparts. Mechanistically, we demonstrate that p38 MAPK/JNK activation is not required for anti-leukemia activities of anisomycin. Instead, anisomycin displays preferential inhibitory effects to Wnt/β-catenin-mediated signaling in CML. Our work provides the preclinical evidence on the potent efficacy of anisomycin in leukemia and its mechanisms of action. Our work suggests that anisomycin is a potential drug to overcome resistance to BCR-ABL TKI treatment in blast phase CML.
Insights
Anisomycin, a clinically available drug, effectively targets chronic myeloid leukemia (CML) cells and enhances tyrosine kinase inhibitor (TKI) efficacy. This combination therapy shows promise for treating blast phase-CML, even when TKIs are less effective alone.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Chronic myeloid leukemia (CML) treatment relies on BCR-ABL tyrosine kinase inhibitors (TKIs).
- TKIs show limited efficacy as single agents in blast phase-CML.
- Novel therapeutic strategies are needed to overcome TKI resistance in advanced CML.
Purpose of the Study:
- To investigate the efficacy of anisomycin as a single agent and in combination with TKIs against CML.
- To elucidate the mechanisms underlying anisomycin's anti-leukemic activity.
- To evaluate anisomycin's potential in overcoming TKI resistance in blast phase-CML.
Main Methods:
- In vitro studies using CML cell lines and primary CD34+ cells from CML patients.
- Colony formation and serial replating assays to assess stem cell function.
- Combination studies with imatinib and dasatinib.
- Mechanistic studies involving signaling pathway analysis (p38 MAPK/JNK, Wnt/β-catenin).
Main Results:
- Anisomycin demonstrated dose-dependent inhibition of CML cell proliferation and induction of apoptosis.
- Anisomycin selectively targeted CML CD34+ stem/progenitor cells, inhibiting their differentiation, proliferation, and self-renewal.
- Combination therapy with anisomycin and TKIs significantly improved efficacy compared to TKIs alone, with reduced toxicity to normal cells.
- Anisomycin's anti-leukemic effects were mediated through inhibition of Wnt/β-catenin signaling, independent of p38 MAPK/JNK activation.
Conclusions:
- Anisomycin exhibits potent anti-leukemic activity against CML cells at all stages, including stem/progenitor cells.
- Anisomycin enhances the efficacy of BCR-ABL TKIs and shows selective toxicity towards CML cells.
- Anisomycin represents a promising therapeutic agent for overcoming TKI resistance in blast phase-CML.
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