Integrative Regulatory Therapy Research

Chapter 8: The IRT Anti-Inflammatory Therapies

The Oasis of Hope IRTs make use of three anti-inflammatory drugs, each of which has been in use for decades: salsalate, disulfiram, and diclofenac. These drugs are used to target key proteins that, in many cancers, promote cancer growth and spread while inducing resistance to chemotherapy or radiotherapy.

Pro-inflammatory Factors

One of these targets is known as "NF-kappaB". This protein complex regulates the synthesis of a number of other proteins by binding to DNA in the cellular nucleus. In a high proportion of advanced cancers, NF-kappaB is either continuously activated or is rapidly activated in response to chemotherapy (1-5). One of the most important roles of NF-kappaB is to boost the production of a number of proteins that act in a variety of ways to prevent the process of apoptosis. This is the "cell suicide" process that is the most common way in which cytotoxic anti-cancer drugs kill cancer cells (6). Moreover, NF-kappaB also increases production of a "multidrug resistance" membrane protein that functions to "pump" various cytotoxic chemicals, including many anti-cancer drugs, out of cells (7). For these reasons, NF-kappaB activation, either chronic, or triggered by chemotherapy, tends to protect cancer cells during chemotherapy. Conversely, many studies show that inhibitors of NF-kappaB activity can make resistant cancer cells much more sensitive to chemotherapy and/or radiation (8-11).

Chronic activation of NF-kappaB also makes cancers act more aggressively. This reflects: increased production of "angiogenic factors" that promote the development of new blood vessels required for cancer growth; increased production of proteolytic enzymes which enable cancer cells to penetrate and migrate through tissues; and increased production of certain factors that promote rapid cellular multiplication (12). The bottom line is that cancers, which have evolved high NF-kappaB activity, tend to spread more rapidly and aggressively, and they are harder to kill off.

Another cancer protein which Oasis of Hope IRT’s target is cyclooxygenase-2, more conveniently referred to as "cox-2". Cox-2 is an enzyme that functions to generate a group of hormone-like compounds known as prostanoids, many of which have inflammatory and pain-promoting activity. That's why inhibitors of cox-2 are frequently used to treat inflammatory conditions. However, many cancers also express elevated activity of cox-2 (13). Some of the prostanoids it produces have growth factor activity for these cancers (14). This growth factor activity promotes increased cancer proliferation, boosts angiogenesis, and also can make cancers harder to kill (15-19). Furthermore, some prostanoids have local immunosuppressive activity that blunts the effectiveness of immune cells that attack the tumor (20).

It should be noted that both NF-kappaB and cox-2 play a direct role in angiogenesis. Activation of these factors occurs in endothelial cells – the cells that give rise to new blood vessels - during the angiogenic process. Agiogenesis is required for efficient production of new blood vessels (21-23). Thus, inhibition of these proteins has the potential to directly suppress angiogenesis by targeting endothelial cell function.

As if NF-kappaB weren’t already pernicious enough for cancer patients, this factor is now known to be a key mediator of the muscle protein loss associated with cancer cachexia (24). Thus, effective inhibition of NF-kappaB likely has the potential to help cancer patients preserve their muscle mass.

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Salsalate

Fortunately, several drugs are available which can suppress the activity of either NF-kappaB or cox-2. One of these is salicylic acid, a natural compound found in white willow bark that has been used for many decades to treat inflammatory disorders such as rheumatoid arthritis. In the late nineteenth century, German chemists first synthesized aspirin (acetylsalicylic acid) by adding an acetyl group to salicylic acid. Salicylic acid, like aspirin, can inhibit cyclooxygenase enzymes, but its activity in this regard is very weak and reversible, for which reason salicylic acid doesn’t produce the dangerous side effects sometimes seen with chronic use of aspirin or related drugs, such as bleeding stomach ulcers or kidney damage (25-27). It is now known that the anti-inflammatory effects of high-dose salicylic acid are more likely to reflect inhibition of NF-kappaB activation. Salicylic acid binds to and inhibits an enzyme that is usually required for NF-kappaB activation (28,29).

Although pharmaceutical companies are working feverishly to develop expensive new inhibitors of NF-kappaB, few medical scientists have considered the possibility of using natural, inexpensive salicylate in cancer therapy (30). There is however recent research establishing that salicylate has cancer-retardant and anti-angiogenic activity. At Oasis of Hope, we believe that salicylic acid has considerable potential for use in cancer therapy, to potentiate the efficacy of chemotherapy in certain cancers, to slow the growth and spread of cancer during at-home therapy, and to slow or prevent the progression of cachexic muscle degeneration (31,32).

Several pharmaceutical forms of salicylic acid are available. We have chosen to use salsalate, a complex which is broken down in the intestinal tract to release free salicylic acid, which is then absorbed (33). Salsalate is less likely to induce gastric irritation that other forms of salicylic acid. It was developed in Japan about 50 years ago, and has been in use since that time for treatment of inflammatory disorders. Salsalate won’t produce dangerous toxicity when used as directed. However, in optimally effective anti-inflammatory doses, it can produce reversible ear dysfunction – tinnitus and mild hearing loss (34). Fortunately, these problems resolve as soon as the drug is discontinued, and no permanent damage is done. For the occasional patient in whom these side effects are highly troubling, a dosage reduction can often solve the problem. It is necessary to use these high doses to achieve effective inhibition of NF-kappaB.

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Disulfiram

Another drug with potential for inhibiting NF-kappaB is disulfiram – the drug more commonly known as "Antabuse". This drug was developed many years ago to help alcoholics abstain from alcohol. If they drink alcohol while using Antabuse, they become ill, owing to increased blood levels of the alcohol metabolite acetaldehyde. More recently, it has been discovered that disulfiram can inhibit cellular components known as proteasomes (35,36). Proteasomes are responsible for degrading cellular proteins which have been specifically targeted for degradation. They play a crucial role in the activation of NF-kappaB by degrading a protein that inhibits this activation. Thus, inhibition of proteasome function usually decreases NF-kappaB activity (37). Recent studies show that disulfiram and related sulfur-containing compounds can inhibit proteasomes and thereby suppress NF-kappaB activity in cancer cells. This renders them less aggressive and more susceptible to eradication (36). In usual clinical doses, disulfiram is a reasonably well tolerated drug as long as the patient does not drink any alcoholic beverage. The dose-limiting toxicity is gastrointestinal upset.

Diclofenac

With respect to cox-2, there are many drugs, commonly referred to as NSAIDs, which can inhibit this enzyme. Some of these drugs are relatively selective to cox-2 – including the prominently advertised drugs Vioxx and Celebrex. In other words, these drugs have little impact on the other form of cyclooxygenase (cox-1). Prolonged effective inhibition of cox-1 can lead to serious complications such as bleeding stomach ulcerations and kidney damage. For that reason, pharmaceutical companies developed cox-2-specific inhibitors for use in the treatment of inflammatory disorders.

Instead of using the expensive, highly advertised and relatively new cox-2-specific inhibitors Celebrex or Vioxx, we at Oasis of Hope have decided to use a much older drug, diclofenac. Diclofenac has an activity spectrum nearly identical to that of Celebrex, producing effective inhibition of cox-2 in concentrations that only modestly impact cox-1, but it is much less expensive (38). When administered in standard clinical doses, diclofenac is more effective than Vioxx at inhibiting cox-2 in the human body (39). While diclofenac has recently been shown to increase heart attack risk like other cox-2-specific inhibitors do (40), we always use it in conjunction with low-dose aspirin, which likely will largely offset that risk.

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