5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells

Kiziltepe, Tanyel, Hideshima, Teru, Catley, Laurence, Raje, Noopur, Yasui, Hiroshi, Shiraishi, Norihiko, Okawa, Yutaka, Ikeda, Hiroshi, Vallet, Sonia, Pozzi, Samantha, Ishitsuka, Kenji, Ocio, Enrique M., Chauhan, Dharminder and Anderson, Kenneth C. (2007) 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Molecular Cancer Therapeutics, 6 6: 1718-1727. doi:10.1158/1535-7163.MCT-07-0010


Author Kiziltepe, Tanyel
Hideshima, Teru
Catley, Laurence
Raje, Noopur
Yasui, Hiroshi
Shiraishi, Norihiko
Okawa, Yutaka
Ikeda, Hiroshi
Vallet, Sonia
Pozzi, Samantha
Ishitsuka, Kenji
Ocio, Enrique M.
Chauhan, Dharminder
Anderson, Kenneth C.
Title 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
1538-8514
Publication date 2007-06
Year available 2007
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-07-0010
Volume 6
Issue 6
Start page 1718
End page 1727
Total pages 10
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Collection year 2008
Language eng
Formatted abstract
In this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage - related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC50 of ∼0.8-3 μmol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine-induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine-induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine-induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM.
Keyword Overcomes Drug Resistance
Hematologic Malignancies
Molecular Mechanisms
Growth factor
Radiosensitizing Agent
Damage Checkpoints
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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