title: Antineoplastic effect of decoy oligonucleotide derived from MGMT enhancer.
abstract: Silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors, mainly through promoter methylation, correlates with a better therapeutic response and with increased survival. Therefore, it is conceivable to consider MGMT as a potential therapeutic target for the treatment of cancers. Our previous results demonstrated the pivotal role of NF-kappaB in MGMT expression, mediated mainly through p65/NF-kappaB homodimers. Here we show that the non-canonical NF-KappaB motif (MGMT-kappaB1) within MGMT enhancer is probably the major inducer of MGMT expression following NF-kappaB activation. Thus, in an attempt to attenuate the transcription activity of MGMT in tumors we designed locked nucleic acids (LNA) modified decoy oligonucleotides corresponding to the specific sequence of MGMT-kappaB1 (MGMT-kB1-LODN). Following confirmation of the ability of MGMT-kB1-LODN to interfere with the binding of p65/NF-kappaB to the NF-KappaB motif within MGMT enhancer, the efficacy of the decoy was studied in-vitro and in-vivo. The results of these experiments show that the decoy MGMT-kB1-LODN have a substantial antineoplastic effect when used either in combination with temozolomide or as monotherapy. Our results suggest that MGMT-kB1-LODN may provide a novel strategy for cancer therapy.
authors.affiliation: Leslie 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.
authors.forename: Tamar
authors.initials: T
authors.lastname: Canello
authors.affiliation: Leslie 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.
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
authors.affiliation: Leslie 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.
authors.forename: Miri
authors.initials: M
authors.lastname: Refael
authors.affiliation: Leslie 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zrihan
authors.affiliation: Leslie 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.
authors.forename: Tali
authors.initials: T
authors.lastname: Siegal
authors.affiliation: Leslie 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.
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015552:Injections, Intralesional; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D009841:Oligonucleotides; D012333:RNA, Messenger; C477371:locked nucleic acid; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide