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Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

ABSTRACT: Bone marrow microenvironment mediated downregulation of BCL6 is critical for maintaining cell quiescence and modulating therapeutic response in B-cell acute lymphoblastic leukemia (ALL). In the present study, we have performed a high throughput cell death assay using BCL6 knockdown REH ALL cell line to screen a library of FDA-approved oncology drugs. In the process, we have identified a microtubule inhibitor, cabazitaxel (CAB), and a RNA synthesis inhibitor, plicamycin (PLI) as potential anti-leukemic agents. CAB and PLI inhibited cell proliferation in not only the BCL6 knockdown REH cell line, but also six other ALL cell lines. Furthermore, combination of CAB and PLI had a synergistic effect in inhibiting proliferation in a cytarabine-resistant (REH/Ara-C) ALL cell line. Use of nanoparticles for delivery of CAB and PLI demonstrated that the combination was very effective when tested in a co-culture model that mimics the in vivo bone marrow microenvironment that typically supports ALL cell survival and migration into protective niches. Furthermore, exposure to PLI inhibited SOX2 transcription and exposure to CAB inhibited not only Mcl-1 expression but also chemotaxis in ALL cells. Taken together, our study demonstrates the utility of concomitantly targeting different critical regulatory pathways to induce cell death in drug resistant ALL cells.

SUBMITTER: Nair RR

PROVIDER: S-EPMC6414069 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

Nair Rajesh R RR Piktel Debbie D Geldenhuys Werner J WJ Gibson Laura F LF

Leukemia research 20180806

Bone marrow microenvironment mediated downregulation of BCL6 is critical for maintaining cell quiescence and modulating therapeutic response in B-cell acute lymphoblastic leukemia (ALL). In the present study, we have performed a high throughput cell death assay using BCL6 knockdown REH ALL cell line to screen a library of FDA-approved oncology drugs. In the process, we have identified a microtubule inhibitor, cabazitaxel (CAB), and a RNA synthesis inhibitor, plicamycin (PLI) as potential anti-le ...[more]

PMID: 30103201

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Project description:BACKGROUND:Drug-resistant cell lines, established from drug-sensitive cell lines by drug exposure in vitro, are the most useful cancer models in studies on the mechanism of chemoresistance. However, the success rate of the traditional approaches to construct such cell lines is low because a long time is required for the addition of drugs. METHODS:A cell culture technique was used to establish the drug-resistant cell lines from their parental cells. Molecular and cellular biological techniques including flow cytometry, MTT assay, western blotting, and DNA fingerprinting analysis were used to characterize the drug-resistant cell lines. Nude mice were used for xenograft studies. RESULTS:We established novel glucocorticoid (GC)-resistant cell lines from 3 GC-sensitive acute lymphoblastic leukemia (ALL) cell lines. First, we established a novel GC-resistant T-ALL cell line, CEM-C7/HDR, by mimicking the microenvironment of the bone marrow and culturing GC-sensitive CEM-C7-14 cells under hypoxia for 5?weeks with a single dexamethasone (Dex) treatment. The CEM-C7/HDR cells had been cultured continuously in drug-free medium under normoxia for 1?year. The IC50 and resistance index (RI) to Dex were maintained at 60~70??M and 1500~1800, respectively, which is in consistent with the IC50 and RI of GC-resistant CEM-C1-15 cells. To clarify the reliability of the method, we subcloned CEM-C7-14 cells, and obtained Dex-resistant cell lines, CEM-C7-SC2/HDR and CEM-C7-SC14/HDR, from 2 monoclonal cells of CEM-C7-14 by the same method. Moreover, we obtained two additional Dex-resistant B-ALL cell lines, NALM-6/HDR and HXEX-ALL1/HDR, from NALM-6 and HXEX-ALL1 cells with the same approach. CONCLUSIONS:CEM-C7/HDR, NALM-6/HDR and HXEX-ALL1/HDR cell lines may serve as useful GC-resistant ALL models for both in vitro and in vivo studies. Culturing under hypoxic condition with a single Dex treatment is a novel and convenient approach for generating stable GC resistant cell lines.

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Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

Publications

Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

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