Abstract
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells. Fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. These results suggest that targeting PHBs could be a new therapeutic strategy for AML.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignant disorder resulting from genetic alterations that lead to deregulation of proliferation, differentiation and cell death in hematopoietic progenitors [1]
In the present study we describe that the prohibitingbinding compound fluorizoline induces apoptosis in acute myeloid leukemia (AML) cells, including a series of primary samples
Our results suggest that PHB has a pro-survival role in AML that is inhibited by the selective binding of fluorizoline
Summary
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignant disorder resulting from genetic alterations that lead to deregulation of proliferation, differentiation and cell death in hematopoietic progenitors [1]. Complete remission is often achieved after high-intensity chemotherapy in younger patients with AML, 5-year overall survival rate is about 40%, since most patients become resistant to chemotherapy and frequently relapse. For these patients with relapsed/ refractory disease therapeutic options are limited [1,2,3]. Accumulating evidence indicates that incomplete eradication of aberrant self-renewal and drug-refractory leukemia stem cells (LSC) in bone marrow (BM) niche sites is responsible for disease relapse [4]. New targets and innovative, more potent drugs are urgently needed to improve both clinical outcomes and long-term quality of life, especially for poor-risk patients and those not eligible for intensive treatment or BM transplantation
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