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Repositioning of bromocriptine for treatment of acute myeloid leukemia

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12967-016-1007-5) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Bromocriptine treatment spared healthy blood cells. a Healthy CD33-positive myeloid mature cells from peripheral blood of healthy donors were treated for 72 h with vehicle control or 10 µM bromocriptine. Cell viability was measured by flow cytometry. b Lineage-depleted umbilical cord blood cells were treated with vehicle control or 10 µM bromocriptine for 18 h and cultured in methylcellulose. Total number of colonies (left) or frequency of each colony subtype (right) refer to control is represented. Bars represent mean value of at least biological triplicates. Error bars correspond to SEM. ***p < 0.005; ****p < 0.001
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Fig3: Bromocriptine treatment spared healthy blood cells. a Healthy CD33-positive myeloid mature cells from peripheral blood of healthy donors were treated for 72 h with vehicle control or 10 µM bromocriptine. Cell viability was measured by flow cytometry. b Lineage-depleted umbilical cord blood cells were treated with vehicle control or 10 µM bromocriptine for 18 h and cultured in methylcellulose. Total number of colonies (left) or frequency of each colony subtype (right) refer to control is represented. Bars represent mean value of at least biological triplicates. Error bars correspond to SEM. ***p < 0.005; ****p < 0.001

Mentions: To demonstrate the differential effect of bromocriptine in AML cells versus healthy blood cells, mature myeloid cells isolated from peripheral blood of healthy donors, as AML normal counterpart, were treated with bromocriptine in the same conditions as were AML cells. As shown in Fig. 3a, no significant effect was detected in cell viability. Thus, bromocriptine treatment spared healthy blood cells. Besides, bromocriptine treatment had no significant effect on the clonogenic capacity of hematopoietic stem/progenitor cells (isolated from lineage-negative umbilical cord blood) both in terms of total number of colonies formed and relative frequency of each colony subtype (Fig. 3b). Taken together, bromocriptine differentially acted as an anti-AML drug that spared the healthy counterpart, especially fighting against the most primitive cell population within the tumor bulk.Fig. 3


Repositioning of bromocriptine for treatment of acute myeloid leukemia
Bromocriptine treatment spared healthy blood cells. a Healthy CD33-positive myeloid mature cells from peripheral blood of healthy donors were treated for 72 h with vehicle control or 10 µM bromocriptine. Cell viability was measured by flow cytometry. b Lineage-depleted umbilical cord blood cells were treated with vehicle control or 10 µM bromocriptine for 18 h and cultured in methylcellulose. Total number of colonies (left) or frequency of each colony subtype (right) refer to control is represented. Bars represent mean value of at least biological triplicates. Error bars correspond to SEM. ***p < 0.005; ****p < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015257&req=5

Fig3: Bromocriptine treatment spared healthy blood cells. a Healthy CD33-positive myeloid mature cells from peripheral blood of healthy donors were treated for 72 h with vehicle control or 10 µM bromocriptine. Cell viability was measured by flow cytometry. b Lineage-depleted umbilical cord blood cells were treated with vehicle control or 10 µM bromocriptine for 18 h and cultured in methylcellulose. Total number of colonies (left) or frequency of each colony subtype (right) refer to control is represented. Bars represent mean value of at least biological triplicates. Error bars correspond to SEM. ***p < 0.005; ****p < 0.001
Mentions: To demonstrate the differential effect of bromocriptine in AML cells versus healthy blood cells, mature myeloid cells isolated from peripheral blood of healthy donors, as AML normal counterpart, were treated with bromocriptine in the same conditions as were AML cells. As shown in Fig. 3a, no significant effect was detected in cell viability. Thus, bromocriptine treatment spared healthy blood cells. Besides, bromocriptine treatment had no significant effect on the clonogenic capacity of hematopoietic stem/progenitor cells (isolated from lineage-negative umbilical cord blood) both in terms of total number of colonies formed and relative frequency of each colony subtype (Fig. 3b). Taken together, bromocriptine differentially acted as an anti-AML drug that spared the healthy counterpart, especially fighting against the most primitive cell population within the tumor bulk.Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: 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&rsquo;s disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.

Results: 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.

Conclusions: 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12967-016-1007-5) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus