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 IκB kinase-β, a central mediator of NF-κB activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with highdose 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-κB activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-κB 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.

Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells

“…Likewise, HDI-induced cell death can be augmented by inhibiting the antiapoptotic transcription factor NF-κB (24,25), whose activation is blocked by aspirin and salicylic acid (26,27). It is currently under discussion that salicylates and other NSAIDs in general may have synergistic efficacy when combined with anticancer agents (28,29). However, there are also a number of studies that suggest otherwise.…”

Inhibitors of NF-κB signaling: 785 and counting

“…However, at higher concentrations, aspirin has also been shown to block NF-kB activity by directly binding to and inhibiting the kinase activity of IKKb by reducing its ability to bind ATP (Yin et al, 1998); more recently, aspirin has also been reported to inhibit proteasome activity and consequently to interfere with degradation of IkB (Dikshit et al, 2006). As such, high-dose aspirin therapy may have applications to diseases where NF-kB activity is involved, including cancer (McCarty and Block, 2006), diabetes (Yuan et al, 2001) and heart disease (Li and Fang, 2004).…”

Toward a Core Nutraceutical Program for Cancer Management

“…143 The possible utility of high-dose aspirin in cachexia prevention is of particular interest in light of the fact that this drug, via joint inhibition of NF-κB and both cox isoforms, may have potential for inhibiting the malignant behavior of many cancers while increasing their apoptotic responsiveness to cytotoxic therapy and slowing angiogenesis. 144 The possibility that silymarin and TTM might also influence cachexia via NF-κB modulation is worthy of consideration, although it is unclear whether these agents affect NF-κB in skeletal muscle.…”