Selective leukemic-cell killing by a novel functional class of thalidomide analogs.
Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-kappaB (NF-kappaB) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of "redoxreactive" thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy.
Ge
Yun
Y
The Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20892-4605, USA.
Montano
Idalia
I
Rustici
Gabriella
G
Freebern
Wendy J
WJ
Haggerty
Cynthia M
CM
Cui
Wenwu
W
Ponciano-Jackson
Damaris
D
Chandramouli
G V R
GV
Gardner
Erin R
ER
Figg
William D
WD
Abu-Asab
Mones
M
Tsokos
Maria
M
Jackson
Sharon H
SH
Gardner
Kevin
K
D020013:Calcium Signaling / Q000187:drug effects* / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004721:Endoplasmic Reticulum / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy / Q000276:immunology*; D008928:Mitochondria / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D050778:NFATC Transcription Factors / Q000276:immunology; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D013792:Thalidomide