1. Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine in anaplastic large cell lymphoma
- Author
-
Irene Steiner, Karoline Kollmann, Martin Bilban, Veronika Sexl, Gerda Egger, Melanie R. Hassler, Aleksandra Klisaroska, and Ana-Iris Schiefer
- Subjects
NPM-ALK, nucleophosmin-anaplastic lymphoma kinase ,DNA Methyltransferase Inhibitor ,M.SssI, CpG methyltransferase ,Biochemistry ,Mice ,0302 clinical medicine ,JAK/STAT, Janus kinase/signal transducer and activator of transcription ,hemic and lymphatic diseases ,Anaplastic lymphoma kinase ,T-cell lymphoma ,Anaplastic Lymphoma Kinase ,DNA (Cytosine-5-)-Methyltransferases ,Enzyme Inhibitors ,NPM-ALK ,AML, acute myeloid leukemia ,Anaplastic large-cell lymphoma ,0303 health sciences ,Anaplastic large cell lymphoma ,HE, hematoxylin and eosin ,General Medicine ,3. Good health ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,COBRA, Combined Bisulfite Restriction Analysis ,DNA methylation ,Azacitidine ,Lymphoma, Large-Cell, Anaplastic ,Female ,5-Aza-CdR, 5-aza-2′-deoxycytidine ,5-Aza-2′-deoxycytidine ,Research Paper ,DNA (Cytosine-5-)-Methyltransferase 1 ,PI3-K/AKT, phosphatidylinositol-3 kinase/AKT ,Antineoplastic Agents ,Biology ,DNA methyltransferase inhibitor ,Decitabine ,03 medical and health sciences ,CML, chronic myeloid leukemia ,PLCγ, phospholipase Cγ ,Cell Line, Tumor ,DNMT1, DNA methyltransferase 1 ,medicine ,Animals ,Humans ,ALCL, anaplastic large cell lymphoma ,Epigenetics ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Proliferation ,030304 developmental biology ,PBMCs, peripheral blood mononuclear cells ,Cell growth ,ALK, anaplastic lymphoma kinase ,Receptor Protein-Tyrosine Kinases ,DNA Methylation ,medicine.disease ,Xenograft Model Antitumor Assays ,Molecular biology ,DNMT1 ,Cancer research ,Transcriptome ,MAPK, mitogen-activated protein kinase - Abstract
DNA methylation is an epigenetic mechanism establishing long-term gene silencing during development and cell commitment, which is maintained in subsequent cell generations. Aberrant DNA methylation is found at gene promoters in most cancers and can lead to silencing of tumor suppressor genes. The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) is able to reactivate genes silenced by DNA methylation and has been shown to be a very potent epigenetic drug in several hematological malignancies. In this report, we demonstrate that 5-aza-CdR exhibits high antineoplastic activity against anaplastic large cell lymphoma (ALCL), a rare CD30 positive non-Hodgkin lymphoma of T-cell origin. Low dose treatment of ALCL cell lines and xenografted tumors causes apoptosis and cell cycle arrest in vitro and in vivo. This is also reflected in genome-wide expression analyses, where genes related to apoptosis and cell death are amongst the most affected targets of 5-aza-CdR. Furthermore, we observed demethylation and re-expression of p16INK4A after drug administration and senescence associated β-galactosidase activity. Thus, our data provide evidence that 5-aza-CdR is highly efficient against ALCL and warrants further clinical evaluation for future therapeutic use., Highlights ► The DNMT inhibitor 5-aza-CdR inhibits growth of ALCL in vitro and in vivo. ► The tumor suppressor p16INK4A is reactivated after treatment. ► Cellular senescence is induced after 5-aza-CdR administration in vitro. ► Genes related to apoptosis, immune response and cell adhesion are main targets.
- Full Text
- View/download PDF