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. 2019 May;7(5):e613.
doi: 10.1002/mgg3.613. Epub 2019 Mar 19.

Sodium butyrate and panobinostat induce apoptosis of chronic myeloid leukemia cells via multiple pathways

Affiliations

Sodium butyrate and panobinostat induce apoptosis of chronic myeloid leukemia cells via multiple pathways

Xiaoyuan Jia et al. Mol Genet Genomic Med. 2019 May.

Abstract

Purpose: Histone deacetylase inhibitor (HDACI) is a novel therapeutic option for cancer. However, the effects of HDACIs on chronic myeloid leukemia (CML) and the underlying mechanisms are still unknown. The aim of this study was to investigate the effect and the mechanism-of-action of two HDACI members, sodium butyrate (NaBu) and panobinostat (LBH589) in K562 and the adriamycin-resistant cell line K562/ADR.

Methods: Cell viability was assessed using MTT assay. Cell apoptosis was detected with flow cytometry. Cell cycle analysis and western blot were performed to explore the possible molecules related to HDACIs effects.

Results: The effect of NaBu was more powerful on K562/ADR than on K562 cells. LBH589 triggered apoptosis and inhibited the growth of K562 cells. Both HDACIs inhibited K562 and K562/ADR cells via activation of intrinsic/extrinsic apoptotic pathways and inhibition of AKT-mTOR pathway while NaBu also activated endoplasmic reticulum stress (ERS) mediated apoptotic pathway in K562/ADR cells. LBH589 reduced the expression of drug-resistant related proteins in K562 cells. However, neither NaBu nor LBH589 could significantly influence the expression of the drug-resistant related proteins in K562/ADR cells.

Conclusion: The combination of HDACI and other therapeutic strategies are likely required to overcome drug resistance in CML therapy.

Keywords: AKT-mTOR pathway; apoptosis; chronic myeloid leukemia (CML); drug resistance; histone deacetylase inhibitors (HDACIs).

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Conflict of interest statement

The authors report no conflict of interest in this work.

Figures

Figure 1
Figure 1
HDACIs inhibited cell proliferation and induced cell apoptosis of K562 cells. Cell survival rates were measured at 48 hr and 72 hr using the MTT assay after treatment with different concentrations of NaBu (a) and LBH589 (b). The results represent the mean of at least three independent experiments. Data are presented as mean ± SD. (c) The apoptosis of K562 cells was analyzed using flow cytometry after treatment of NaBu and LBH589. Cells were treated with 2 mmol/L NaBu or 100 nmol/L LBH589 for 24 hr, and apoptosis status was analyzed using Annexin V‐FITC and PI double staining. Early apoptotic cells are Annexin V+/PI, and late apoptotic and dead cells are Annexin V+/PI+
Figure 2
Figure 2
LBH589 activated the apoptosis related proteins in K562 cells. Cells were treated with 2 mmol/L NaBu or 100 nmol/L LBH589 for 24 hr. (a) The expressions of caspase 9/8/7/6/3 and PARP were significantly induced by the treatment of the two HDACIs. (b) The expressions of BCL‐2 family proteins were influenced by the treatment of the two HDACIs. (c) As the members of the inhibitor of apoptosis family of proteins (IAP), XIAP and survivin were down‐regulated by the treatment of HDACIs
Figure 3
Figure 3
HDACIs inhibited the activity of AKT‐mTOR signaling pathway in K562 cells. Cells were treated with 2 mmol/L NaBu or 100 nmol/L LBH589 for 24 hr. (a) The expressions of key proteins in AKT‐mTOR signaling pathway were dramatically changed after treatment of HDACIs; (b) Transcription factor c‐MYC was down‐regulated by HDACIs treatment
Figure 4
Figure 4
NaBu arrested cell cycle in G0/G1 phase. (a) The treatment of 2 mmol/L NaBu caused a significant increase in the G0/G1 fraction of the cell cycle in K562 cells, while 100 nmol/L LBH589 failed to perturb cell cycle obviously; (b) Quantification of cell cycle analysis. Data were presented as mean ± SD, *p < 0.05
Figure 5
Figure 5
The effects of HDACIs on K562/ADR cells. Cells were treated with 2 mmol/L NaBu or 100 nmol/L LBH589 for 24 hr. (a) NaBu significantly inhibited the proliferation of K562/ADR cells while LBH589 had a moderate effect on the cells; (b) Neither NaBu nor LBH589 could suppress the expression of drug–resistance related proteins in K562/ADR cells, while LBH589 down‐regulated the expression of ABCG2, BCR/ABL and p‐BCR/ABL in K562 cells; (c) NaBu significantly induced apoptosis in K562/ADR cells; (d and e) Neither of the HDACIs exhibited cell cycle arrest in K562/ADR cells
Figure 6
Figure 6
NaBu induced K562/ADR cells apoptosis via intrinsic, extrinsic, ERS–mediated pathways and AKT‐mTOR pathway. (a, b and c) The effects of HDACIs on apoptotic related proteins in K562/ADR cells; (d and e) NaBu inhibited the activity of AKT‐mTOR pathway and down‐regulated the expression of c‐MYC in K562/ADR cells

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