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Targeting leukemia cell metabolism
Full text linkRecent evidences show that malignant cell undergo a metabolic reprogramming, acquiring new bioenergetic phenotypes. These new metabolic features grant them the capability of sustaining expensive processes such as cell growth and proliferation. Among the metabolic pathways involved, an increased glycolytic flux, the exploitation of alternative carbon source like glutamine, and an increase in fatty acid metabolism may be included. Metabolic reprogramming is strictly related to aberrant activation of signal transduction pathways, but the causal relationship between altered signalling and redesigned metabolism is currently under review, based on recent works showing a feedback mechanism, in which metabolites are involved in controlling signal fluxes through specific sensor kinases which monitor the cell bioenergetic status. Therefore, cancer cell metabolism represents a potential target for therapeutic intervention that may be integrated with conventional chemotherapy and molecularly targeted agents. In solid tumors, a great number of studies supports the potential of this approach while only few are published in hematologic malignancies.
With the aim of extending the knowledge of leukemia cell metabolic phenotypes, we studied the role of the main catabolic pathways, such as glycolysis, glutaminolysis and fatty acid oxidation.
This study involved the use of metabolic inhibitors, in order to identify novel molecular therapeutic strategies in hematological malignancies.
Dichloroacetate (DCA) is a pyruvate-mimetic molecule, which acts as pyruvate dehydrogenase kinase (PDHK) inhibitor, thus activating pyruvate dehydrogenase (PDH). This activation causes a shift in leukemic cell metabolism, from aerobic glycolysis to glucose oxidation. Our results documented that acute myeloid leukemia (AML) cells are characterized by higher rates of glycolysis compared to normal cells and that the use of DCA, an inhibitor of glycolysis, acts in a short time (30-60 minutes), increasing the levels of oxidative phosphorylation and, in a longer time, reducing cell growth and inducing apoptosis in cells of AML.
Aminooxyacetic Acid (AOA) is a cellular transaminase inhibitor. This compound is able to inhibit the conversion from glutamate to α-ketoglutarate, second step of the glutaminolytic process.
ST1326 is an aminocarnitine derivative, able to block the activity of CPT1a, the enzyme which catalyze the rate-limiting step of fatty acid oxidation. The results obtained in our in vitro study showed a high pro-apoptotic activity of this inhibitor in models of cell lines and primary cells from acute leukemia.
Overall, these preclinical results demonstrate the role of cell metabolism as a potential therapeutic target in hematologic malignancies, warranting further extension of this strategy
Modulation of glycolytic metabolism by dichloroacetate induces apoptosis in acute myeloid leukemia cells
No full textPI3K inhibition by BKM120 on acute myeloid leukemia: a preclinical study
No full textAcute myeloid leukemia (AML) patients are often characterized by deregulation of various intracellular signaling pathways, including PI3K/Akt/mTOR, which concur to increased cell proliferation and abnormal survival. Stagnation of clinical results, especially in patients not eligible for aggressive treatment, have prompted the investigation on novel targeted therapies. Currently, several PI3K/Akt/mTOR inhibitors, especially those targeting downstream signals, have been investigated in AML. However, reactivation of critical upstream nodes have been associated with reduced activity of these molecules. BKM120 is a novel pan-class I PI3K inhibitor, characterized by a significant cell growth inhibition and apoptosis in a variety of solid tumors. Therefore, we investigated preclinically the activity of BKM120 on several acute leukemia (AL) cell lines and on primary AML samples.
BKM120, kindly provide by Novartis, was tested on different leukemia cell models (U937, HL60, MOLM13) and primar
Modulation of the glycolytic metabolism in acute myeloid leukemia cells
No full textGlycolysis is the central axis of cellular metabolism. The cancer cell bioenergetic status heavily relies on high glycolytic rates, even in aerobic conditions, thus sustaining the expensive processes of cell growth and proliferation. Growing evidences show that signaling aberrations - especially those involving PI3K/Akt/mTOR, HIF1a, Ras/Raf/MEK/ERK - are strictly connected to the establishment of a pro-glycolytic metabolism, through a multi-level crosstalk between proteins and metabolites that contribute to the acquisition of an energetic background granting a proliferative advantage. Here we investigated the glycolytic rate of resting and activated normal peripheral blood lymphocytes (NPBLs) and of acute myeloid leukemia (AML) cell lines. In an attempt to modulate the cellular metabolism for therapeutic intervention, we tested the following compounds that directly interfere with major metabolic or signaling pathways: dichloroacetate (DCA), a glycolysis inhibitor; aminooxyacetate (AOA
The phosphatidylinositol-3-kinase inhibitor BKM120 impairs proliferation and induces pro-apoptotic effects in acute myeloid leukemia
No full textAcute myeloid leukemia (AML) has been characterized by a growing number of recurrent genetic alterations, frequently causing the constitutive activation of signal transduction pathways, which result in enhanced blast proliferation and prolonged survival. Despite the increased understanding of AML biology, prognosis of these patients remains, generally, severe. Therefore, novel therapies targeted on aberrant signaling are now under evaluation. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the control of cell growth, proliferation and apoptosis of AML, and is often found constitutively activated. Currently, several inhibitors of this pathway, especially those inhibiting the activity of mTOR, have been investigated showing a limited efficacy due to the reactivation of upstream nodes. Since a novel PI3K inhibitor, BKM120, has been evaluated with encouraging results on solid tumors and lymphoid malignancies, we aimed in t
Fatty acid oxidation and metabolic targeting of leukemia cells by the CPT1 inhibitor ST1326
No full textThe sustained rate of proliferation of cancer cells requires metabolic adaptation to satisfy the increased energetic demand and the need of biosynthetic precursors. Growing evidences show that tumor cells adopt enhanced rate of glycolysis and divert fluxes from alternative substrates, such as glutamine and fatty acid (FA), to sustain anabolic processes. Targeting the metabolic reprogramming of neoplastic cells may result in an effective novel approach for pharmacological intervention. In order to evaluate in acute leukemias this strategy, we preliminary measured cellular FA uptake differences between normal and leukemia cells, by flow cytometry using a fluorescent fatty acid analog (BODIPY-C12). Thereafter, taking advantage of ST1326 (Sigma Tau), a molecule capable of selectively and reversibly inhibiting Carnitine Palmitoyl-Transferase 1 (CPT1), a protein catalyzing the FA import into the mitochondria, we evaluated the effectiveness of FA oxidation targeting in acute leukemias. The c
Novel Histone Deacetylase (HDAC) inhibitors: in vitro effects on leukemic cells
No full textHistone deacetylase inhibitors (HDAC-I) are a group of small molecules that have been intensively investigated in a variety of malignancies because of their ability to induce a broad range of effects preferentially on cancer cells, including cell cycle arrest, apoptosis, cell differentiation, autophagy and anti-angiogenic effects. However, clinical responses have been obtained only in a proportion of patients, prompting further studies aimed at identifying more active compounds. Here we investigated the effects of two new HDAC-I, MS-275 and ST7612AA1 (doses ranging from 5 to 5000nM) on cell proliferation and apoptosis in acute leukemia cell line models (U937, MOLT4, Jurkat, Raji) and on freshly isolated AML samples. The cytotoxic effects were assessed by MTT assay. The drug concentration inducing 50% cell killing (IC-50) was calculated from the dose-response curve. Cell cycle inhibition and induction of apoptosis were analyzed by flow cytometry using the Acridine-Orange (AO) and Anne
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