Venetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia.
J Cell Mol Med
; 26(9): 2646-2657, 2022 05.
Article
in En
| MEDLINE
| ID: mdl-35355406
ABSTRACT
Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT-330 (Selinexor) and Bcl-2 inhibitor venetoclax (ABT-199) in preclinical models of AML, which was partially meditated by Mcl-1, although the full mechanism of action remains unknown. In this study, using real-time RT-PCR and Western blot analysis, we show that inhibition of XPO1 via KPT-330 or KPT-8602 (Eltanexor) decreases the mRNA and protein levels of c-Myc, CHK1, WEE1, RAD51 and RRM2. KPT-330 and KPT-8602 induce DNA damage, as determined by alkaline comet assay. In addition, we demonstrate that venetoclax enhances KPT-330- and KPT-8602-induced DNA damage, likely through inhibition of DNA damage repair. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Myeloid, Acute
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
J Cell Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2022
Document type:
Article
Affiliation country: