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Antineoplastic effect of decoy oligonucleotide derived from MGMT enhancer
Tamar Canello1, Haim Ovadia1, Miri Refael1
1Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Plos One
|December 3, 2014
Summary
Silencing O(6)-methylguanine-DNA-methyltransferase (MGMT) improves cancer therapy. A novel locked nucleic acid decoy (MGMT-kB1-LODN) targeting the MGMT enhancer shows significant anti-cancer effects alone or with temozolomide.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Silencing O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors correlates with better therapeutic response and survival.
- MGMT is a potential therapeutic target for cancer treatment.
- NF-kappaB signaling, particularly p65/NF-kappaB homodimers, plays a key role in regulating MGMT expression.
Purpose of the Study:
- To investigate the role of the non-canonical NF-kappaB motif (MGMT-kappaB1) in the MGMT enhancer as a major inducer of MGMT expression.
- To design and evaluate locked nucleic acid (LNA) modified decoy oligonucleotides (MGMT-kB1-LODN) to inhibit MGMT transcription.
- To assess the anti-cancer efficacy of MGMT-kB1-LODN in vitro and in vivo.
Main Methods:
- Design of LNA-modified decoy oligonucleotides (MGMT-kB1-LODN) targeting the MGMT-kappaB1 motif.
- Confirmation of MGMT-kB1-LODN's ability to interfere with p65/NF-kappaB binding to the MGMT enhancer.
- In vitro and in vivo studies to evaluate the anti-cancer efficacy of MGMT-kB1-LODN.
Main Results:
- The MGMT-kappaB1 motif within the MGMT enhancer is identified as a key regulator of MGMT expression upon NF-kappaB activation.
- MGMT-kB1-LODN effectively interferes with p65/NF-kappaB binding to the MGMT enhancer.
- MGMT-kB1-LODN demonstrated substantial antineoplastic effects as monotherapy and in combination with temozolomide.
Conclusions:
- MGMT-kB1-LODN represents a novel strategy to attenuate MGMT transcription activity in tumors.
- This decoy oligonucleotide shows significant potential for cancer therapy, offering a new therapeutic avenue.
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