Selective leukemic-cell killing by a novel functional class of thalidomide analogs.

Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Research Abstract Details 

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Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Abstract Text:

Yun Ge,Idalia Montano,Gabriella Rustici,Wendy J Freebern,Cynthia M Haggerty,Wenwu Cui,Damaris Ponciano-Jackson,G V R Chandramouli,Erin R Gardner,William D Figg,Mones Abu-Asab,Maria Tsokos,Sharon H Jackson,Kevin Gardner,

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.

Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Publishing Authors By Initials

Y Ge,I Montano,G Rustici,WJ Freebern,CM Haggerty,W Cui,D Ponciano-Jackson,GV Chandramouli,ER Gardner,WD Figg,M Abu-Asab,M Tsokos,SH Jackson,K Gardner,

For similar organic chemicals: carboxylic acids: acids, carbocyclic: phthalic acids: phthalimides: thalidomide research abstracts see: organic chemicals: carboxylic acids: acids, carbocyclic: phthalic acids: phthalimides: thalidomide research

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Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Blood

VOLUME: 108

Page Numbers: 4126-35

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 29

MONTH: 08

YEAR: 2006

Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7603509

Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Keywords Mesh Terms:

KEYWORDS: Thalidomide

MESH TERMS: therapeutic use

Chemical & Substance for Abstract: Selective leukemic-cell killing by a novel functional class of thalidomide analogs. Information

Substance Name: Thalidomide

Registry Number: 50-35-1

Grant and Affiliation Information for Selective leukemic-cell killing by a novel functional class of thalidomide analogs.

AFFILIATION: The Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20892-4605, USA.

Country: United States

AGENCY: United States NCI

GRANT: N01-CO-12400

ACRONYM: CO

MEDLINETA: Blood

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