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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4126-4135.
Prepublished online as a Blood First Edition Paper on August 29, 2006; DOI 10.1182/blood-2006-04-017046.
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Submitted April 13, 2006
Accepted August 3, 2006
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, and Kevin Gardner*
Laboratory of Receptor Biology and Gene, National Cancer Institute, Bethesda, MD
Clinical Pharmacology Research Core, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD
Center for Cancer Research, National Cancer Institute, Bethesda, MD
Laboratory of Pathology, National Cancer Institute, Bethesda, MD
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
* Corresponding author; email: gardnerk{at}mail.nih.gov.
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 anti-leukemic activity. These agents activate nuclear factor of activated T-cells (NFAT) transcriptional pathways while simultaneously repressing NF- B 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, reversed by free radical scavengers, synergizes with the anti-leukemic activity or other redox directed compounds, and preferentially target cells in S-phase of the cell cycle. Live cell imaging reveals a rapid drug-induced burst of reactive oxygen species originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of " redox reactive" 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.
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