Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9Reportar como inadecuado

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Journal of Hematology and Oncology

, 8:46

First Online: 08 May 2015Received: 16 January 2015Accepted: 27 April 2015DOI: 10.1186-s13045-015-0143-3

Cite this article as: Chau, D., Ng, K., Chan, T.SY. et al. J Hematol Oncol 2015 8: 46. doi:10.1186-s13045-015-0143-3


BackgroundThe therapeutic efficacy of arsenic trioxide As2O3 in acute myeloid leukemia AML is modest, which is partly related to its limited intracellular uptake into the leukemic cells. As2O3 enters cells via the transmembrane protein aquaglyceroporin 9 AQP9. Azacytidine, a demethylating agent that is approved for the treatment of AML, has been shown to have synergistic effect with As2O3. We tested the hypothesis that azacytidine might up-regulate AQP9 and enhances As2O3-mediated cytotoxicity in AML.

MethodsArsenic-induced cytotoxicity, the expression of AQP9, and the intracellular uptake of As2O3 were determined in AML cell lines and primary AML cells with or without azacytidine pre-treatment. The mechanism of AQP9 up-regulation was then investigated by examining the expression of transcription factors for AQP9 gene and the methylation status of their gene promoters.

ResultsAs2O3-induced cytotoxicity in AML cell lines was significantly enhanced after azacytidine pre-treatment as a result of AQP9 up-regulation, leading to increased arsenic uptake and hence intracellular concentration. Blocking AQP9-mediated As2O3 uptake with mercury chloride abrogated the sensitization effect of azacytidine. AQP9 promoter does not contain CpG islands. Instead, azacytidine pre-treatment led to increased expression of HNF1A, a transcription activator of AQP9, through demethylation of HNF1A promoter. HNF1 knockdown abrogated azacytidine-induced AQP9 up-regulation and almost completely blocked intracellular As2O3 entry, confirming that azacytidine enhanced As2O3-mediated cell death via up-regulation of HNF1A and hence increased AQP9 and As2O3 intracellular concentration. Azacytidine sensitization to As2O3 treatment was re-capitulated also in primary AML samples. Finally, azacytidine did not enhance arsenic toxicity in a liver cell line, where HNF1A was largely unmethylated.

ConclusionsAzacytidine sensitizes AML cells to As2O3 treatment, and our results provide proof-of-principle evidence that pharmacological up-regulation of AQP9 potentially expands the therapeutic spectrum of As2O3. Further clinical trial should evaluate the efficacy of azacytidine in combination with As2O3 in the treatment of AML.

KeywordsAcute myeloid leukemia Arsenic trioxide Azacytidine Demethylating agents Aquaglyceroporin 9 David Chau and Karen Ng contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13045-015-0143-3 contains supplementary material, which is available to authorized users.

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Autor: David Chau - Karen Ng - Thomas Sau-Yan Chan - Yuen-Yee Cheng - Bonnie Fong - Sidney Tam - Yok-Lam Kwong - Eric Tse


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