Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO.

Abstract

Synthetic triterpenoids, such as 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its derivatives, are an extremely potent class of new anti-cancer therapeutic agents, characterized by high anti-tumor potency and low toxicity to normal tissues. This report is the first to investigate the effects of C-28 derivatives of CDDO on 22 pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. We determined IC(50)s in the range of 5-170 nM for inhibition of colony formation and DNA synthesis, and 110-630 nM for metabolic cell death and decrease in cell number, using the C-28 CDDO analogs, CDDO methyl ester (CDDO-Me), CDDO imidazolide (CDDO-Im), CDDO ethyl amide (CDDO-EA), CDDO trifluoroethyl amide (CDDO-TFEA), and CDDO diethylamide (CDDO-DE). After treatment of human neuroblastoma cells with CDDO-Me, cell cycle studies show depletion of the S-phase, while apoptosis studies show conformational activation and mitochondrial translocation of Bax protein, as well as activation of caspases -3 and -8. These data demonstrate the potential utility of CDDO analogs as promising novel therapeutic agents for high-risk pediatric solid tumors.

• Authors: Jennifer L Alabran, Adam Cheuk, Karen Liby, Michael Sporn, Javed Khan, John Letterio, Konstantin S Leskov
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 7 Issue 5 Pg. 709-17 (May 2008) ISSN: 1555-8576 [Electronic] United States
• PMID: 18277094 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• Terpenes
• Oleanolic Acid

Topics

• Apoptosis
• Brain Neoplasms (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Chemistry, Pharmaceutical (methods)
• Cytosol (metabolism)
• Drug Design
• Humans
• Inhibitory Concentration 50
• Mitochondria (metabolism)
• Models, Chemical
• Neuroblastoma (drug therapy, metabolism)
• Oleanolic Acid (analogs & derivatives, chemistry, pharmacology)
• Protein Transport
• Terpenes (chemistry)