title: Selective leukemic-cell killing by a novel functional class of thalidomide analogs.
abstract: 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.
authors.affiliation: The Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20892-4605, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ge
authors.forename: Idalia
authors.initials: I
authors.lastname: Montano
authors.forename: Gabriella
authors.initials: G
authors.lastname: Rustici
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Freebern
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Haggerty
authors.forename: Wenwu
authors.initials: W
authors.lastname: Cui
authors.forename: Damaris
authors.initials: D
authors.lastname: Ponciano-Jackson
authors.forename: G V R
authors.initials: GV
authors.lastname: Chandramouli
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Jackson
authors.forename: Kevin
authors.initials: K
authors.lastname: Gardner
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D013792:Thalidomide