title: Sensitization of tumor cells toward chemotherapy: enhancing the efficacy of camptothecin with imidazolines.
abstract: Activation of nuclear transcription factor kappaB (NF-kappaB) by chemotherapeutic agents was found to protect cells from apoptosis. In light of its central role in regulating the cellular resistance to apoptotic agents, inhibition of NF-kappaB-mediated gene transcription may sensitize tumor cells to chemotherapeutic agents and enhance their efficacy. We describe herein a noncytotoxic imidazoline scaffold that sensitizes leukemia T cells to the chemotherapeutic agent camptothecin. No significant induction of apoptosis was found when cells were treated with the imidazoline; however, pretreatment of cells with this agent resulted in a drastic enhancement in efficacy of camptothecin (approximately 75-fold). Elucidation of the potential cellular mechanism revealed that the imidazoline prevents nuclear translocation of NF-kappaB. These findings indicate that inhibition of NF-kappaB by this imidazoline may present improved strategies in the chemotherapeutic treatment of cancer.
authors.affiliation: Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sharma
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lansdell
authors.forename: Satyamaheshwar
authors.initials: S
authors.lastname: Peddibhotla
authors.forename: Jetze J
authors.initials: JJ
authors.lastname: Tepe
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D048288:Imidazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D008156:Luciferases / Q000032:analysis; D008954:Models, Biological; D008968:Molecular Conformation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D012680:Sensitivity and Specificity
chemical_list: D020672:I-kappa B Proteins; D048288:Imidazolines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D002166:Camptothecin