Abstract
Myeloid leukemia is a hematologic neoplasia characterized by a clonal proliferation of hematopoietic stem cell progenitors. Patient prognosis varies depending on the subtype of leukemia as well as eligibility for intensive treatment regimens and allogeneic stem cell transplantation. Although significant progress has been made in the therapy of patients including novel targeted treatment approaches, there is still an urgent need to optimize treatment outcome. The most common therapy is based on the use of chemotherapeutics cytarabine and anthrayclines. Here, we studied the effect of the recently synthesized marine alkaloid 3,10-dibromofascaplysin (DBF) in myeloid leukemia cells. Unsubstituted fascaplysin was early found to affect cell cycle via inhibiting CDK4/6, thus we compared the activity of DBF and other brominated derivatives with known CDK4/6 inhibitor palbociclib, which was earlier shown to be a promising candidate to treat leukemia. Unexpectedly, the effect DBF on cell cycle differs from palbociclib. In fact, DBF induced leukemic cells apoptosis and decreased the expression of genes responsible for cancer cell survival. Simultaneously, DBF was found to activate the E2F1 transcription factor. Using bioinformatical approaches we evaluated the possible molecular mechanisms, which may be associated with DBF-induced activation of E2F1. Finally, we found that DBF synergistically increase the cytotoxic effect of cytarabine in different myeloid leukemia cell lines. In conclusion, DBF is a promising drug candidate, which may be used in combinational therapeutics approaches to reduce leukemia cell growth.
Highlights
Myeloid leukemia is a group of heterogeneous malignant disorders characterized by uncontrolled clonal proliferation of primitive hematopoietic stem or progenitor cells
Potential targets for treating myeloid leukemias comprise receptors of tyrosine kinases [9,10,11,12], proteins contributing to the drug resistance and mutated proteins [13,14], kinases involved in pro-survival signaling pathways [11,13,15,16], components of DNA-reparation system [17,18] as well as kinases involved in cell cycle regulation and autophagy [19,20,21]
We found that treatment with DBF leads to a reduction of CCNA1 and CCND2 gene expression encoding Cyclin A1 and Cyclin D2 in all Importantly, treatment with DBF significantly affected genes TP53 and BCL2 encoding p53 and BCL2 family proteins related to cancer pathophysiology and resistance to conventional chemotherapy [35,36,37,38,39]
Summary
Myeloid leukemia is a group of heterogeneous malignant disorders characterized by uncontrolled clonal proliferation of primitive hematopoietic stem or progenitor cells. This disease is divided into two subgroups according to the type of affected blood cell and its chronic or acute forms and include acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Potential targets for treating myeloid leukemias comprise receptors of tyrosine kinases [9,10,11,12], proteins contributing to the drug resistance and mutated proteins [13,14], kinases involved in pro-survival signaling pathways [11,13,15,16], components of DNA-reparation system [17,18] as well as kinases involved in cell cycle regulation and autophagy [19,20,21]. The inhibitor is assumed to be an attractive therapeutic option for elderly AML patients who are unable to tolerate high-dose
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