Preadministration of high-dose salicylates, suppressors of NF-kappa B activation, may increase the chemosensitivity of many cancers: An example of proapoptotic signal modulation therapy

NF-kappa B 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-kappa B promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-kappa B also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-kappa B activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-kappa B activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-kappa B 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 I kappa B kinase, a central mediator of NF-kappa B 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 salicylate 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-kappa B activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-kappa B 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 angiogenesis by targeting cycling endothelial cells in tumors.