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: Vasudha Sharma, Theresa A Lansdell, Satyamaheshwar Peddibhotla, Jetze J Tepe
• Journal: Chemistry & biology (Chem Biol) Vol. 11 Issue 12 Pg. 1689-99 (Dec 2004) ISSN: 1074-5521 [Print] United States
• PMID: 15610853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• I-kappa B Proteins
• Imidazolines
• NF-kappa B
• NFKBIA protein, human
• NF-KappaB Inhibitor alpha
• Luciferases
• Camptothecin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Camptothecin (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• I-kappa B Proteins (drug effects, metabolism)
• Imidazolines (chemical synthesis, pharmacology)
• Leukemia, T-Cell (drug therapy, metabolism)
• Luciferases (analysis)
• Models, Biological
• Molecular Conformation
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, metabolism)
• Phosphorylation
• Sensitivity and Specificity