Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy.
NF-kappaB 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-kappaB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-kappaB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-kappaB activity appears to be largely responsible for the chemo- and radioresistance of many cancers. Thus, agents that suppress NF-kappaB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-kappaB 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 Ikappa kinase- beta, a central mediator of NF-kappa 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-kappa activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-kappa 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.
McCarty
Mark F
MF
Block Center for Integrative Cancer Care, Evanston, Illinois 60201, USA.
Block
Keith I
KI
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D020360:Neoadjuvant Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012459:Salicylates / Q000008:administration & dosage / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D016328:NF-kappa B; D012459:Salicylates