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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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-κB (NF-κB) 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.

Original languageEnglish
Pages (from-to)4126-4135
Number of pages10
Issue number13
StatePublished - 15 Dec 2006


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