Korean J Physiol Pharmacol.  2025 Jan;29(1):67-81. 10.4196/kjpp.24.176.

Mebendazole effectively overcomes imatinib resistance by dualtargeting BCR/ABL oncoprotein and ββ-tubulin in chronic myeloid leukemia cells

• Yang L
• Du Z
• Peng Y
• Zhang W
• Feng W
• Yuan Y

• KMID: 2563501
• DOI: http://doi.org/10.4196/kjpp.24.176

Abstract

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Keyword

Chronic myeloid leukemia; Drug repositioning; Imatinib resistance; Mebendazole

Figure

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  Fig. 1 Mebendazole (MBZ) inhibits proliferation and induces apoptosis of CML cells. (A–C) Dose-response curve for IM and MBZ in K562 and K562/G01 using CCK-8 assay after incubation for 48 h. (D) Dose-response curve for MBZ in bone marrow stromal cell line HS-5 using CCK-8 assay after incubation for 48 h. (E) The cell proliferative activity of CML cells treated with MBZ for 7 days was assessed using a colony formation assay. The scale bar represents 25 μm. (F) The colony formation rate was calculated and statistically analyzed. (G) The apoptosis levels of CML cells were evaluated using annexin-V-FITC/PI labeling and FCM after MBZ treatment for 24 h. (H) The cell apoptosis rate was analyzed based on the FCM results. (I) The protein expression levels of PARP, Caspase-3, and their corresponding cleaved bands were measured using a western blot. (J, K) The expression levels of Bax, Bcl-2, and Bcl-XL were detected by western blot, and the ratio of Bcl-2/Bax was calculated. The values are the mean and SD of three independent experiments. CML, chronic myeloid leukemia; IM, imatinib; PI, propidium iodide; FCM, flow cytometry; ns, no significance. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 vs. the control group.

• 

  Fig. 2 Mebendazole (MBZ) suppresses BCR/ABL kinase activity and downstream signaling pathways by binding the ATP-binding site of BCR/ABL kinase. (A, B) Western blot was used to measure protein expression of BCR/ABL, p-BCR/ABL, STAT5, p-STAT5 and signaling molecules in the RAS/RAF/MEK/ERK signaling pathway after MBZ treatment for 24 h. (C) In vitro validation of protein kinase inhibition by MBZ. Staurosporine was used as a positive control to inhibit the kinase activity of ABL1. The values are the mean ± SD of three independent experiments. (D) The molecular structure of MBZ. (E) The molecular structure of imatinib. (F) The binding pose and interactions of imatinib (magenta) with co-crystallized BCR/ABL kinase in the crystal structure (PDB ID: 1IEP) and predicted docking orientation of imatinib (yellow) in silico docking analysis. (G) The predicted binding pose of MBZ (red) in BCR/ABL tyrosine kinase (green, PDB ID: 1IEP) with a binding affinity of −9.0 kcal/mol. Key amino acid residues are visualized in sticks. Hydrogen bonds (green), hydrophobic interactions (pink), π-stacking (cyan) and salt bridges (yellow) are indicated as dashed lines.

• 

  Fig. 3 Mebendazole (MBZ) induces aberrant mitosis and multinucleation in CML cells. (A, B) Cell cycle distribution was measured and analyzed using FCM. (C) The expression levels of cell cycle-associated proteins c-MYC, p21 and Cyclin B1 in CML cells treated with MBZ for 24 h were detected by western blot. (D, F) Morphological changes were observed by Liu’s staining after incubation with MBZ for 24 h (D) and 36 h (F). The scale bar represents 10 μm. (E, G) Mitotic index was determined by the proportion of mitotic cells after treatment with MBZ for 24 h and multi-nucleated cells were counted after 48 h (in a total of at least 100 cells in at least two random fields). The values are represented as the mean ± SD of three independent experiments. CML, chronic myeloid leukemia; FCM, flow cytometry; ns, no significance. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 vs. the controls.

• 

  Fig. 4 Mebendazole (MBZ) disrupts microtubule organization and leads to tubulin polymerization. (A, E) DMSO; (B, F) 0.1 μM MBZ; (C, G) 0.5 μM MBZ; (D, H) 1.0 μM MBZ. CML cells were treated with the indicated concentrations of MBZ for 24 h, and the alternation of microtubule organization and distribution was observed by fluorescence confocal microscopy. The scale bar represents 10 μm. (I) The protein level of α-tubulin in CML cells was detected by western blot. Tubulin polymerization assay was utilized to evaluate the polymerized (P) and soluble (S) α-tubulin in K562 cells (J) and K562/G01 cells (K) after incubated with MBZ, colchicine (Col), or paclitaxel (PTX) at indicated concentrations. The percentage of polymerized α-tubulin in K562 cells (L) and K562/G01 cells (M) was determined using the formula: %P = P/(P + S). The values are the mean ± SD of four independent experiments. CML, chronic myeloid leukemia; DMSO, dimethyl sulfoxide; ns, no significance. *p < 0.05 and **p < 0.01 vs. the controls.

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  Fig. 5 Mebendazole (MBZ) effectively interacts with the colchicine-binding site of β-tubulin. (A, B) β-tubulin protein levels in CML cells were detected using CETSA and the quantitative data were shown on the right. The values are the mean ± SD of three independent experiments. (C) Molecular structures of colchicine. (D) The binding pose of colchicine (orange) with tubulin in the crystal structure (PDB ID: 4O2B) and predicted orientation of colchicine (green) in silico docking analysis. (E) The predicted binding orientation and interactions of MBZ (red) in the α/β-tubulin heterodimer (purple, PDB ID: 4O2B) with a binding affinity of −10.1 kcal/mol. Key amino acid residues are visualized in sticks. Hydrogen bonds (green), and hydrophobic interactions (pink) are indicated as dashed lines. (F) The levels of active β-tubulin and EBI: β-tubulin adduct were detected by CETSA and western blot. CML, chronic myeloid leukemia; CETSA, cellular thermal shift assay; EBI, N, N′-ethylenebis(iodoacetamide); DMSO, dimethyl sulfoxide.

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  Fig. 6 Mebendazole (MBZ) enhanced DNA damage by hindering the recruitment of ATM and DNA-PKcs in the nucleus. (A, B) The alternation of the cellular location and protein levels of γH2AX in CML cells after treatment with MBZ for 24 h was screened by immunofluorescence and western blot. The scale bar represents 10 μm. (C) The levels of ROS were evaluated by FCM. *p < 0.05 vs. the control group. (D) The expression levels of DNA repair protein ATM and DNA-PKcs were assessed by western blot. (E, F) Nuclear and cytoplasmic protein extraction assay was performed and followed by western blot to analyze the cellular accumulation of ATM (E) and DNA-PKcs (F) in the cytoplasm (C) and nucleus (N) in K562/G01 cells. ATM, ataxia-telangiectasia mutated; DNA-PKcs, DNA-dependent protein kinase; CML, chronic myeloid leukemia; ROS, reactive oxygen species; FCM, flow cytometry; ns, no significance.

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  Fig. 7 Schematic diagram of the function and mechanisms of MBZ in CML cells. The anticancer effect of MBZ is mediated by at least two processes: one involving downregulated p-BCR/ABL and its downstream signaling pathways, and the other involving disrupted microtubule dynamics. This molecule downregulates p-BCR/ABL, p-STAT5 and MAPK signalling pathway, thereby inhibiting the growth of CML cells. MBZ blocks microtubule polymerization, results in cell cycle arrest at mitosis and triggers mitotic catastrophe event, which induces apoptosis in CML cells. In addition, MBZ triggers substantial DNA damage by delaying repair processing, leading to enhanced genomic instability and mitotic catastrophe. MBZ, mebendazole; CML, chronic myeloid leukemia; ATM, ataxia-telangiectasia mutated; DNA-PKcs, DNA-dependent protein kinase.

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