Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

Chen, Ping; Aimiuwu, Josephine; Xie, Zhiliang; Wei, Xiaohui; Liu, Shujun; Klisovic, Rebecca B.; Marcucci, Guido; Chan, Kenneth K.

doi:10.1208/s12248-010-9246-5

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…C/EBPα, CCAAT/enhancer binding protein α; FLT3, FMS-like tyrosine kinase-3; HK3, hexokinase 3; KLF5, krüppel-like factor 5. Ara-C treatment, various novel drug combinations have been explored (70,71). Recently, it was demonstrated that miR-181a could sensitize a chemotherapy-resistant HL60 cell line to Ara-C treatment (72).…”

Section: Regulators Targeting C/ebpα In Myeloid Differentiation and Lmentioning

confidence: 99%

Regulation of the C/EBPα signaling pathway in acute myeloid leukemia (Review)

Song

Wang

et al. 2015

Oncology Reports

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The transcription factor CCAAT/enhancer binding protein α (C/EBPα), as a critical regulator of myeloid development, directs granulocyte and monocyte differentiation. Various mechanisms have been identified to explain how C/EBPα functions in patients with acute myeloid leukemia (AML). C/EBPα expression is suppressed as a result of common leukemia-associated genetic and epigenetic alterations such as AML1-ETO, RARα-PLZF or gene promoter methylation. Recent data have shown that ubiquitination modification also contributes to its downregulation. In addition, 10-15% of patients with AML in an intermediate cytogenetic risk subgroup were characterized by mutations of the C/EBPα gene. As a transcription factor, C/EBPα can translocate into the nucleus and further regulate a variety of genes directly or indirectly, which are all key factors for cell differentiation. This review summarizes recent reports concerning the dysregulation of C/EBPα expression at various levels in human AML. The currently available data are persuasive evidence suggesting that impaired abnormal C/EBPα expression contributes to the development of AML, and restoration of C/EBPα expression as well as its function represents a promising target for novel therapeutic strategies in AML.

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Section: Regulators Targeting C/ebpα In Myeloid Differentiation and Lmentioning

confidence: 99%

Regulation of the C/EBPα signaling pathway in acute myeloid leukemia (Review)

Song

Wang

et al. 2015

Oncology Reports

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“…41,42 To improve the cytotoxic activity of Ara-C treatment, various novel drug combinations have been explored. 43,44 Recently, it was demonstrated that miR-181a can sensitize a chemotherapyresistant HL60 cell line to Ara-C treatment. 29 Having found that miR-181a is up-regulated in response to lenalidomide, we asked whether pretreatment of AML cells with this compound can similarly sensitize the cells to Ara-C.…”

mentioning

confidence: 99%

Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia

Hickey¹,

Schwind²,

Radomska³

et al. 2013

Blood

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• High miR-181a levels associate with CEBPA mutations and likely contribute to the favorable prognostic impact of these mutations in AML. • Lenalidomide induces CEBPA-dependent miR-181a expression and in turn increases sensitivity to chemo-therapy in AML blasts. Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBP transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBP-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the mi-croRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBP-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumori-genic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBP-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy. (Blood. 2013;121(1):159-169)

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“…23 In this study, aCD33LN/GTI-2040 and Ara-C were evaluated as a combination in Kasumi-1 and K562 cells. IC 50 values were determined by MTS assay.…”

Section: Resultsmentioning

confidence: 99%

“…Prior studies have indicated a therapeutic benefit of combining GTI-2040 with Ara-C in the treatment of AML. 23 In this study, aCD33LN/GTI-2040 and Ara-C were evaluated as a combination in Kasumi-1 and K562 cells. IC 50 values were determined by MTS assay.…”

Section: Cd33 Expression and Acd33lnmentioning

confidence: 99%

CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia

Quan

et al. 2015

Mol. Pharmaceutics

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CD33-targeted lipid nanoparticles (aCD33LNs) were synthesized for delivery of GTI-2040, an antisense oligonucleotide (ASO) against the R2 subunit of ribonucleotide reductase, to acute myelogenous leukemia (AML). These LNs incorporated a deoxycholate-polyethylenimine (DOC-PEI) conjugate, which has shown significant activity to facilitate oligonucleotide delivery. Anti-CD33 scFv (aCD33) was added as a targeting ligand. The delivery efficiency of this system was investigated both in vitro and in vivo. When cells were treated with aCD33LN/GTI-2040, significant uptake was observed in CD33 positive Kasumi-1 cells. aCD33LNs loaded with GTI-2040 induced significant downregulation of R2 mRNA and protein levels in AML cells. Moreover, aCD33LN/GTI-2040 showed a 15-fold reduction in the IC 50 of antileukemic drug Ara-C in Kasumi-1 cells. In Kasumi-1 xenograft model, aCD33LN/GTI-2040 showed significant R2 downregulation compared to LN/GTI-2040. Furthermore, aCD33LN/GTI-2040 coadministered with Ara-C was shown to be highly effective in tumor growth inhibition and to greatly increase survival time of mice bearing Kasumi-1 xenograft tumors. The conjugate DOC-PEI has shown an ability to include calcein release from lipid nanoparticles, suggesting a potential mechanism contributing to efficient endosome release by DOC-PEI2K. These results indicate that aCD33LNs are a highly effective vehicle for the therapeutic delivery of antisense agents to AML.

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Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

Cited by 5 publications

References 39 publications

Regulation of the C/EBPα signaling pathway in acute myeloid leukemia (Review)

Regulation of the C/EBPα signaling pathway in acute myeloid leukemia (Review)

Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia

CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia

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