The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergizes with imatinib to trigger apoptosis in chronic myeloid leukemia

Pharmacol Res. 2020 Oct:160:105058. doi: 10.1016/j.phrs.2020.105058. Epub 2020 Jun 30.

Abstract

Despite the discovery of tyrosine kinase inhibitors (TKIs) for the treatment of breakpoint cluster region-Abelson (BCR-ABL)+ cancer types, patients with chronic myeloid leukemia (CML) treated with TKIs develop resistance and severe adverse effects. Combination treatment, especially with a histone deacetylase (HDAC) 6 inhibitor (HDAC6i), appears to be an attractive option to prevent TKI resistance, considering the potential capacity of an HDAC6i to diminish BCR-ABL expression. We first validated the in vivo anti-cancer potential of the compound 7b by significantly reducing the tumor burden of BALB/c mice xenografted with K-562 cells, without notable organ toxicity. Here, we hypothesize that the HDAC6i compound 7b can lead to BCR-ABL downregulation in CML cells and sensitize them to TKI treatment. The results showed that combination treatment with imatinib and 7b resulted in strong synergistic caspase-dependent apoptotic cell death and drastically reduced the proportion of leukemia stem cells, whereas this treatment only moderately affected healthy cells. Ultimately, the combination significantly decreased colony formation in a semisolid methylcellulose medium and tumor mass in xenografted zebrafish compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation followed by disturbance of key proteins in downstream pathways involved in CML proliferation and survival. Taken together, our results suggest that an HDAC6i potentiates the effect of imatinib and could overcome TKI resistance in CML cells.

Keywords: 4-hydroxybenzoic acid; Cisplatin (PubChem CID: 441203); Combination chemotherapy; Etoposide (VP-16, PubChem CID: 92209272); Imatinib (PubChem CID: 123596); Imatinib resistance; Leukemia stem cells; Suberanilohydroxamic acid (SAHA, PubChem CID: 5311); Synergistic cytotoxic effect; Tubacin (PubChem CID: 6675804); Tyrosine kinase inhibitor; Z-VAD-FMK (zVAD, PubChem CID: 5737).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspases / drug effects
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Fusion Proteins, bcr-abl / metabolism*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Humans
  • Imatinib Mesylate / pharmacology*
  • Imatinib Mesylate / therapeutic use*
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use*
  • Tumor Stem Cell Assay
  • Ubiquitination / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Caspases
  • HDAC6 protein, human
  • Histone Deacetylase 6