Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2015

Open Access 01-12-2015 | Research article

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

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

Published in: Journal of Hematology & Oncology | Issue 1/2015

Login to get access

Abstract

Background

The 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.

Methods

Arsenic-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.

Results

As2O3-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.

Conclusions

Azacytidine 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.
Appendix
Available only for authorised users
Literature
1.
2.
Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011;29:495–503.CrossRefPubMed
3.
Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.PubMed
4.
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:5328–35.CrossRefPubMedCentralPubMed
5.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.CrossRefPubMed
6.
Au WY, Kumana CR, Lee HK, Lin SY, Liu H, Yeung DY, et al. Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study. Blood. 2011;118:6535–43.CrossRefPubMed
7.
Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science. 2010;328:240–3.CrossRefPubMed
8.
Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008;10:538–46.CrossRefPubMed
9.
Jeanne M, Lallemand-Breitenbach V, Ferhi O, Koken M, Le Bras M, Duffort S, et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell. 2010;18:88–98.CrossRefPubMed
10.
Chen YC, Lin-Shiau SY, Lin JK. Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. J Cell Physiol. 1998;177:324–33.CrossRefPubMed
11.
Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, et al. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res. 1999;249:413–21.CrossRefPubMed
12.
Li H, Wang Y, Xu W, Dong L, Guo Y, Bi K, et al. Arsenic trioxide inhibits DNA methyltransferase and restores TMS1 gene expression in K562 cells. Acta Haematol. 2015;133:18–25.CrossRefPubMed
13.
Tsukaguchi H, Weremowicz S, Morton CC, Hediger MA. Functional and molecular characterization of the human neutral solute channel aquaporin-9. Am J Physiol. 1999;277:F685–96.PubMed
14.
Leung J, Pang A, Yuen WH, Kwong YL, Tse EW. Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Blood. 2007;109:740–6.CrossRefPubMed
15.
Bhattacharjee H, Carbrey J, Rosen BP, Mukhopadhyay R. Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. Biochem Biophys Res Commun. 2004;322:836–41.CrossRefPubMed
16.
Lubbert M, Suciu S, Baila L, Ruter BH, Platzbecker U, Giagounidis A, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–96.CrossRefPubMed
17.
Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–61.CrossRefPubMed
18.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–9.CrossRefPubMed
19.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.CrossRefPubMedCentralPubMed
20.
Peng CY, Jiang J, Zheng HT, Liu XS. Growth-inhibiting effects of arsenic trioxide plus epigenetic therapeutic agents on leukemia cell lines. Leuk Lymphoma. 2010;51:297–303.CrossRefPubMed
21.
Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, et al. Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. Am J Hematol. 2011;86:796–800.CrossRefPubMed
22.
Pang RW, Lee TK, Man K, Poon RT, Fan ST, Kwong YL, et al. PIN1 expression contributes to hepatic carcinogenesis. J Pathol. 2006;210:19–25.CrossRefPubMed
23.
Au WY, Cheung GT, Yuen TW, Kumana CR, Kwong YL. Successful treatment of relapsed acute promyelocytic leukemia in a patient receiving continuous ambulatory peritoneal dialysis with oral arsenic trioxide. Arch Intern Med. 2005;165:1067–8.CrossRefPubMed
24.
Ishibashi K, Kuwahara M, Gu Y, Tanaka Y, Marumo F, Sasaki S. Cloning and functional expression of a new aquaporin (AQP9) abundantly expressed in the peripheral leukocytes permeable to water and urea, but not to glycerol. Biochem Biophys Res Commun. 1998;244:268–74.CrossRefPubMed
25.
Carbrey JM, Song L, Zhou Y, Yoshinaga M, Rojek A, Wang Y, et al. Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice. Proc Natl Acad Sci U S A. 2009;106:15956–60.CrossRefPubMedCentralPubMed
26.
Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci U S A. 2008;105:4826–31.CrossRefPubMedCentralPubMed
27.
Mendel DB, Crabtree GR. HNF-1, a member of a novel class of dimerizing homeodomain proteins. J Biol Chem. 1991;266:677–80.PubMed
28.
Costa RH, Kalinichenko VV, Holterman AX, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38:1331–47.CrossRefPubMed
29.
Kikuchi R, Yagi S, Kusuhara H, Imai S, Sugiyama Y, Shiota K. Genome-wide analysis of epigenetic signatures for kidney-specific transporters. Kidney Int. 2010;78:569–77.CrossRefPubMed
30.
Pastoret A, Marcos R, Sampayo-Reyes A, Saucedo-Cardenas O, Lozano-Garza GH, Hernandez A. Inhibition of hepatocyte nuclear factor 1 and 4 alpha (HNF1alpha and HNF4alpha) as a mechanism of arsenic carcinogenesis. Arch Toxicol. 2013;87:1001–12.CrossRefPubMed
Metadata
Title
Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9
Authors
David Chau
Karen Ng
Thomas Sau-Yan Chan
Yuen-Yee Cheng
Bonnie Fong
Sidney Tam
Yok-Lam Kwong
Eric Tse
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-015-0143-3

Other articles of this Issue 1/2015

Journal of Hematology & Oncology 1/2015 Go to the issue

Research

Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling

Review

Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future

RESEARCH ARTICLE

STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion

Research highlight

Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer

Commentary

Nivolumab plus ipilimumab in the treatment of advanced melanoma

Research

Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits