Exploiting cellular pathways to develop new treatment strategies for AML

Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, Baltimore, MD 21231, USA.
Cancer Treatment Reviews (Impact Factor: 7.59). 04/2010; 36(2):142-50. DOI: 10.1016/j.ctrv.2009.12.004
Source: PubMed


The standard approaches to the treatment of acute myeloid leukemia (AML) have been predominantly based on cytarabine and anthracyclines. Yet, the outcomes associated with AML continue to be poor, especially for those patients who are older or carry higher-risk disease. In recent years, extensive research has led to the development and study of novel agents which target AML by diverse and varied mechanisms. Among these are targeted therapeutics such as kinase inhibitors and oligonucleotide constructs. These aim to suppress the production or activity of proteins, such as FLT3 and BCL2, among others, and thus disrupt related signaling cascades essential for leukemogenesis and proliferation. In addition, other agents like flavopiridol appear to target the myeloid blast by various mechanisms including suppression of cyclin-dependent kinases and interference with nucleotide synthesis. Another class of novel therapies includes inhibitors of histone deacetylase, which cause growth arrest and apoptosis through histone acetylation and resultant conformational changes. Clinical trials are now studying these and other agents alone and in combination with traditional cytotoxic therapies, with some encouraging results. In this review, we aim to provide a summary of the preclinical and clinical investigations of selected promising agents currently under study.

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Available from: Amir Fathi, May 15, 2014
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    • "The standard approach for AML treatment is chemotherapy with cytarabine and anthracyclines ; however, even after aggressive chemotherapy about 75% of AML patients relapse within 2 years of remission [1] [2]. Recently, several targeted cytotoxic approaches to treat AML have been developed, for example, the use of kinase and histone deacetylase inhibitors [3], but such strategy is difficult to apply to AML, since the molecular lesions in AML are highly heterogeneous. "
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    ABSTRACT: Plant polyphenols have been shown to enhance the differentiation of acute myeloid leukemia (AML) cells induced by the hormonal form of vitamin D(3) (1α,25-dihydroxyvitamin D(3); 1,25D). However, how these agents modulate 1,25D effects in different subtypes of AML cells remains poorly understood. Here, we show that both carnosic acid (CA) and silibinin (SIL) synergistically enhancd 1,25D-induced differentiation of myeloblastic HL60 cells. However, in promonocytic U937 cells, only CA caused potentiation while SIL attenuated 1,25D effect. The enhanced effect of 1,25D+CA was accompanied by increases in both the vitamin D receptor (VDR) and retinoid X receptor alpha (RXRα) protein levels and vitamin D response element (VDRE) transactivation in both cell lines. Similar increases were observed in HL60 cells treated with 1,25D + SIL. In U937 cells, however, SIL inhibited 1,25D-induced VDRE transactivation concomitant with downregulation of RXRα at both transcriptional and posttranscriptional levels. These inhibitory effects correlated with the inability of SIL, with or without 1,25D, to activate the Nrf2/antioxidant response element signaling pathway in U937 cells. These results suggest that opposite effects of SIL on 1,25D-induced differentiation of HL60 and U937 cells may be determined by cell-type-specific signaling and transcriptional responses to this polyphenol resulting in differential modulation of RXRα expression.
    05/2012; 2012(6):401784. DOI:10.1155/2012/401784
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    • "The FLT3 receptor consists of an extracellular portion of five immunoglobulin-like domains, a trans-membrane region, a short intracellular juxtamembrane unit, and an intracellular tyrosine kinase domain. Upon binding FLT3 ligand (FL), the receptor dimerizes and the inner leaflet of the membrane is autophosphorylated , which then leads to activation of the tyrosine kinase and subsequent downstream signaling, with significant mediators being PI3-kinase, AKT, MAP kinase, and STAT5 (Figure 1) [18] [19] [20] [21] [22] [23] [24] [25] [26]. In the normal hematopoietic environment, FLT3 expression is predominantly on CD34 expressing cells, and appears to be integrally involved in early hematopoiesis and reconstitution of multi-lineage myeloid precursors [12, 27-29]. "
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    ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.
    American Journal of Blood Research 01/2011; 1(2):175-89.
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    • "Exposure of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 μM) resulted in a marked increase in NF-B DNA binding which is abrogated by coadministration of flavopiridol (100 nM). Thus, flavopiridol potentiates antileukemic activity of HDACIs [200] [201]. "
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    ABSTRACT: Nuclear factor-kappaB (NF-κB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-κB signaling pathway is constitutively activated in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas and in multiple myeloma (MM). Inactive NF-κB is bound in the cytoplasm to its inhibitor IκB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. The overexpression of NF-κB and its anti-apoptotic cytoprotective effect suggest that it might be a useful therapeutic target for the treatment of hematologic malignancies. Several drugs effective for the treatment of MM, including proteasome inhibitors, thalidomide, lenalidomide and arsenic trioxide, block NF-κB activation. New agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents and reduce different side-effects. Triptolide (diterpenoid triepoxyde), a purified component of a traditional Chinese medicine, extracted from a shrub-like vine named Trypterygium wilfordii Hook F (TWHF) inhibits transcriptional activation of NF-κB and downregulates the expression of various NF-κB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-κB activation can be also inhibited by IKKβ-selective inhibitors, PS-1145dihydrochloride, MLN120B (both Millennium Pharmaceuticals, Cambridge, MA) and BMS-345541 (Bristol-Myers Squibb, Princeton, NJ). LC-1, the dimethylamino-parthenolide (DMAPT) derivative demonstrated significant cytotoxicity to AML blasts targeting NF-κB.
    Current Molecular Pharmacology 11/2010; 3(3):98-122. DOI:10.2174/1874210205941874672
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