NFκB inhibitors exhibiting rapid intracellular amplification of reactive oxygen species
As part of a drug discovery program on natural product anticancer agents, tropical plant extracts collected in southeast Asia were tested for cytotoxicity using HT-29 colon cancer cells as a gate-keeper assay, with active extracts then also tested in a NFκB assay. Purified compounds isolated from the active species were tested in both cytotoxicity and NFκB assays [1, 2]. NFκB inhibitors were then tested for their ability to activate nuclear factor of activated T cells (NFAT) transcriptional pathways while also repressing NFκB via a rapid intracellular amplification of reactive oxygen species (ROS) [3–8].
Two quassinoids, bruceantin (1) and bruceine A (2), from Brucea javanica (L.) Merr. (Simaroubaceae), were identified as being representative of a new functional class of redox-reactive compounds characterized by their ability to up-regulate the NFAT transcriptional pathway through the amplification of intracellular ROS [7, 9]. Although oxidative stress plays a well-recognized role in multiple forms of cell death in a variety of tissues, manipulation of ROS as a treatment paradigm in cancer has only recently emerged as a promising new strategy. Some cancer cells, in particular leukemia cells, have a higher susceptibility to elevated ROS that is often enhanced following chemotherapy, possibly secondary to accrued mitochondrial DNA damage . This finding reinforces the emerging paradigm that targeting the redox state can be an effective strategy against cancer and may influence the design and implementation of other agents that exploit similar cell-specific vulnerabilities to chemotherapeutic agents.
Acknowledgements: This research was supported by a new faculty start-up package to E.J.C. de B. and by grant P01 CA125066–01A1 from NCI, NIH to A.D.K. We wish to acknowledge the plant taxonomists who collected the plant material screened in this investigation.
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