RT Journal Article
SR Electronic
T1 Combinatorial Antileukemic Disruption of Oxidative Homeostasis and Mitochondrial Stability by the Redox Reactive Thalidomide 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1<em>H</em>-isoindole-1,3(2<em>H</em>)-dione (CPS49) and Flavopiridol
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 872
OP 883
DO 10.1124/mol.107.040808
VO 74
IS 3
A1 Yun Ge
A1 Jung S. Byun
A1 Paola De Luca
A1 Geraldine Gueron
A1 Idalia M. Yabe
A1 Sara G. Sadiq-Ali
A1 William D. Figg
A1 Jesse Quintero
A1 Cynthia M. Haggerty
A1 Quentin Q. Li
A1 Adriana De Siervi
A1 Kevin Gardner
YR 2008
UL http://molpharm.aspetjournals.org/content/74/3/872.abstract
AB 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-κB (NF-κB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.