Repositioning of bromocriptine for treatment of acute myeloid leukemia.
Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.



An in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson's disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.



Treatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells.



Our results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.
María Carmen
MC
Lara-Castillo
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.
Josep Maria
JM
Cornet-Masana
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.
Amaia
A
Etxabe
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.
Antònia
A
Banús-Mulet
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Miguel Ángel
MÁ
Torrente
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Meritxell
M
Nomdedeu
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
Marina
M
Díaz-Beyá
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain.|Department of Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
Jordi
J
Esteve
Centre Esther Koplowitz, Josep Carreras Leukaemia Research Institute, Campus Clínic-University of Barcelona, Rosselló 149-153, 08036, Barcelona, Spain. risueno@carrerasresearch.org.
Ruth M
0000-0003-4048-9536
RM
Risueño
D000328:Adult; D001971:Bromocriptine / Q000494:pharmacology / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058492:Drug Repositioning; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D039481:CD11b Antigen; D001971:Bromocriptine
AML; Bromocriptine; Drug repositioning; Leukemia stem cells; New drug