Reference : The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergiz...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/47920
The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergizes with imatinib to trigger apoptosis in chronic myeloid leukemia
English
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 mailto [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,]
Jun-2020
Pharmacological Research
Elsevier
160
Yes (verified by ORBilu)
International
1043-6618
1096-1186
Atlanta
GE
[en] Leukemia stem cells ; Imatinib resistance ; Combination chemotherapy
[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.
Researchers
http://hdl.handle.net/10993/47920
10.1016/j.phrs.2020.105058

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Limited access
Losson_2020.pdfPublisher postprint7.8 MBRequest a copy

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.