Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO.
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.
Alabran
Jennifer L
JL
Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cheuk
Adam
A
Liby
Karen
K
Sporn
Michael
M
Khan
Javed
J
Letterio
John
J
Leskov
Konstantin S
KS
D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003600:Cytosol / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D021381:Protein Transport; D013729:Terpenes / Q000737:chemistry
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D013729:Terpenes; D009828:Oleanolic Acid