Article (Scientific journals)
The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergizes with imatinib to trigger apoptosis in chronic myeloid leukemia
Losson, Hélène; Gajulapalli, Sruthi Reddy; Lernoux, Manon et al.
2020In Pharmacological Research, 160
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Keywords :
Leukemia stem cells; Imatinib resistance; Combination chemotherapy
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Losson, Hélène;  Laboratoire de Biologie Moléculaire et Cellulaire du Cancer
Gajulapalli, Sruthi Reddy;  Seoul National University > Department of Pharmacy
Lernoux, Manon;  Laboratoire de Biologie Moléculaire et Cellulaire du Cancer
Lee, Jin-Young;  Seoul National University > Department of Pharmacy
Mazumder, Aloran;  Seoul National University > Department of Pharmacy
GERARD, Déborah  ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Seidel, Carole;  Laboratoire de Biologie Moléculaire et Cellulaire du Cancer ; Université de Lorraine > Faculté de Médicine > Service d’Histologie
Hahn, Hyunggu;  Seoul National University > Department of Pharmacy
Christov, Christo;  Université de Lorraine > Faculté de Médicine > Service d’Histologie
Dicato, Mario;  Laboratoire de Biologie Moléculaire et Cellulaire du Cancer
Kirsch, Gilbert;  Université de Lorraine > UMR CNRS 7053 LC2M
Han, Byung Woo;  Seoul National University > Department of Pharmacy
Schnekenburger, Michael;  Laboratoire de Biologie Moléculaire et Cellulaire du Cancer
Diederich, Marc;  Seoul National University > Department of Pharmacy,
More authors (4 more) Less
External co-authors :
yes
Language :
English
Title :
The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergizes with imatinib to trigger apoptosis in chronic myeloid leukemia
Publication date :
June 2020
Journal title :
Pharmacological Research
ISSN :
1096-1186
Publisher :
Elsevier, Atlanta, Georgia
Volume :
160
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 01 September 2021

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