Antisense anti-MDM2 oligonucleotides as a novel approach to the treatment of glioblastoma multiforme.
Overexpression of the MDM2 oncogene is one of the molecular characteristics of gliomas. In this study we determined the therapeutic effects of an antisense anti-MDM2 oligonucleotide administered alone or in combination with the clinically used chemotherapeutic agents Paclitaxel and Irinotecan. In cultured cells with various p53 status, U87-MG (p53wt/wt), A172 (p53wt/mt) and T98G (p53mt/mt), the antisense oligonucleotide, produced a dose- and sequence-dependent reduction in MDM2 expression and elevation in p53 (in U87-MG and A172 cells) and p21 levels (in all three cell lines), resulting in an increase in apoptosis and cytotoxicity. Synergistic effects on p53 and p21 levels between the oligonucleotide and chemotherapeutic agents were also observed in vitro. In in vivo studies with U87-MG xenografts, the oligonucleotide inhibited tumor growth and improved the therapeutic efficacy of paclitaxel and irinotecan 39- and 63-fold, respectively. In conclusion, inhibiting MDM2 expression could be a novel pharmacological approach to glioblastoma therapy.
Prasad
Gautam
G
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294-0019, USA.
Wang
Hui
H
Agrawal
Sudhir
S
Zhang
Ruiwen
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D017239:Paclitaxel; D002166:Camptothecin