Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

Abstract

NF-κB activity is elevated in a high proportion of cancers, particularly advanced cancers that have been treated previously. Cytotoxic treatment selects for such up-regulation inasmuch as NF-κB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-κB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-κB activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-κB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-κB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits Iκ kinase- β, a central mediator of NF-κ activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with high-dose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicy-late or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo- or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-κ activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-κ antagonists and/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angio-genesis by targeting cycling endothelial cells in tumors.