Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine in solid tumor cells.
Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2'-deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology.
Corresponding Author: Michael Bitzer, Medical University Hospital, University of Tuebingen, Otfried-Mueller-Str. 10, Tuebingen D-72076, Germany. michael.bitzer@uni-tuebingen.de.
Sascha
S
Venturelli
Alexander
A
Berger
Timo
T
Weiland
Frank
F
Essmann
Michaela
M
Waibel
Tina
T
Nuebling
Sabine
S
Häcker
Martin
M
Schenk
Klaus
K
Schulze-Osthoff
Helmut R
HR
Salih
Simone
S
Fulda
Bence
B
Sipos
Ricky W
RW
Johnstone
Ulrich M
UM
Lauer
Michael
M
Bitzer
D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation / Q000235:genetics; D000077209:Decitabine; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine