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

Block Center for Integrative Cancer Care, Evanston, Illinois.

Keith I. Block, MD

Block Center for Integrative Cancer Care, Evanston, Illinois, drblock{at}blockmedical.com

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

Key Words: NF-B • IB kinase-ß • NSAID • aspirin • salicylate • cytotoxic chemotherapy

Integrative Cancer Therapies, Vol. 5, No. 3, 252-268 (2006)
DOI: 10.1177/1534735406291499


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