Coaxing cox

Tags: Knowledge

COX-2 inhibitors, conventional and natural, including curcumin found in turmeric, are every medicine developer’s dream come true

Research wraps up the idea that conventional cyclooxygenase-2 (COX-2), or coxib inhibitors represent an advance — one that provides conventional treatment with a well-defined place in clinical practice. But what bogs down the frenzied enthusiasm is not about efficacy in isolation, or long-term, because coxibs also seem to be more than a match to classical traditional non-steroidal anti-inflammatory drugs (NSAIDs) in easing both acute and chronic pain, besides posing the prospect of certain serious side-effects.

The negatives aside — the amount of information now available to us for arriving at a definitive conclusion in full favour of conventional coxibs is approximate, albeit the basic facts on their efficiency are somewhat mixed, or even controversial. In addition to this, as evidence for damage continues to ascend with traditional, or conventional, NSAIDs in causing deaths — reports suggest that on an average 1 in 1,200 patients taking them for at least four weeks could die from gastro-duodenal complications. Such patients, as clinicians contend, would not have died if they had not taken the medications.

In an editorial published in The Journal of the American Medical Association (JAMA), it was estimated that for low-risk patients for whom the hazard of developing a NSAID-related ulcer complication is 0.4 per cent, the cost of preventing a single complication was $350,000. If the risk is higher, as in elderly patients, or in patients with a prior history of a 5 per cent risk, the cost was $45,000 — what with most, or all, of the costs compensated by co-prescribed acid suppressants. This is a medical paradox, although it may be highlighted that a new faecal test for calprotectin (calprotectin increases in infective or inflammatory conditions) has become handy. The test offers us the possibility to detect and prevent ulcers before they ‘blow’ their gloomy bugle.

It may also be emphasised that conventional NSAIDs and COX-2 inhibitors subdue renal, or kidney, activity. Research suggests that this could be accountable for certain cases of peripheral oedema (swelling) seen in clinical trials. A meta-analysis (research synthesis) on the effect of NSAIDs on post-operative kidney function reports a clinically unimportant and short-lived reduction in renal function with NSAIDs.

In another study, a randomised comparison of coxib drugs, such as rofecoxib and indomethacin, suggested that they caused clinically inconsequential and transitory retention of sodium (excess sodium, or salt, is bad for the kidney), but no slump in kidney filtration rate. In other words, it did not cause any untoward effects on the organ. All the same, most clinicians advise a discreet approach — that it would be perfectly all right to tell patients, on conventional coxib treatment, the prospect of oedema, while keeping a close watch on kidney function.

COX-2 inhibitors, conventional and natural, including curcumin found in turmeric, are every medicine developer’s derring-do, a dream-come-true, as it were. Curcumin, the herbal aspirin, has been shown to inhibit certain growth factors. Every tumour needs blood supply and curcumin seems to impede them. Research suggests that curcumin ‘reawakens’ a key tumour-suppressor gene. It also inhibits metastases, especially in prostate and breast cancer, and quells other cancer cells, besides preventing the re-growth of cancer stem cells which populate the core of several tumours. New research hails curcumin as a ‘holistic’ anti-cancer herb, because of its success in not only halting cancer formation, replication and spread, but also providing the synergy to other anti-cancer drugs, while protecting healthy cells and organs. Research in the UK evidences that curcumin and chokeberry, for instance, can work together to induce cancer cell death (apoptosis) and prevent the spread of malignant cancer cells. Studies also suggest that curcumin can prevent cancer stem cells from re-growing the tumour. Recent research has shown curcumin can dexterously counter the dangerous effects of hormone replacement therapy (HRT) and its hazardous relationship with breast cancer. According to clinicians women could take curcumin supplements to protect themselves from developing progestin-accelerated tumours, primarily because synthetic progestin increases vascular endothelial growth factor (VEGF), a protein that helps form the blood supply to developing tumours. Curcumin inhibits VEGF and, thus, reduces the potential of breast cancer to proliferate.

This is, indeed, the fundamental reason why researchers have, in tune with their scientific finesse, designed coxibs with a definitive purpose: to crush inflammation. But this isn’t all. COX-2 inhibitors have emerged as lead players for preventing cancer, an inflammatory disorder, or its recurrence. Gary J Kelloff, a researcher at the National Cancer Institute (NCI), US, who lists the requirements for a molecular target, such as the COX-2 enzyme, says it must be highly expressed in pre-cancer or cancer cells, and not in others. Blocking it, he adds, isn't harmful, because it doesn’t disrupt normal function. He observes that drug effects must be measurable; so also clinical benefits. His conclusion, “COX-2 is an ideal target.” The use of coxibs for cancer began with the approval of celebrex to treat a certain type of colon cancer, 16 years ago.

Here’s a case in point. Familial adenomatous polyposis (FAP) fits perfectly into NCI’s objective to target cancer in its early stage. The practice is called chemoprevention. With an aging population, better diagnostics, and the promise of proteomics — the study of the proteome = the complete set of proteins produced, using the technologies of large-scale protein separation and identification — it makes practical sense to begin cancer treatment, with the coxib ‘ammo,’ sooner than later, along with traditional, or conventional, management of the disease in FAP.

COX-2 inhibitors are ‘sophisticated’ non-steroidal anti-inflammatory drugs (NSAIDs). According to Makoto M Taketo, a professor of pharmacology at Japan’s Kyoto University Graduate School of Medicine, these “aspirin-like NSAIDs” act pharmacologically — as anti-inflammatory agents and analgesics — and, in so doing, they reduce fever. Coxibs also cause minimal side-effects, unlike aspirin, which causes gastro-intestinal ulceration and bleeding. It is reported that 15,000 patients die from aspirin ‘toxicity,’ in the US alone, every year.

NSAIDs weaken two forms of the coxib enzymes; and, of the two it is only one — COX-1 — which causes adverse effects. They also inhibit COX-2 enzymes, which are synthesised from arachidonic acid in cell membranes. In other words, COX-1, the ‘housekeeping’ variant, is expressed in several cells; it provides the basic functions of life. In contrast, COX-2, which can be, more or less, ‘influenced,’ by means fair and square, is not made in normal epithelium — or, layers of cells that line hollow organs and glands. It causes inflammation and promotes tumour formation in response to growth factors, cytokines — protein molecules, or communication links, between immune system cells — or, oncogene, a gene that can cause a cell to develop into a tumour, or cancer.

COX-2 stimulates the production of a particular type of prostaglandins, which activates a specific epithelium receptor. This activity sets off a process for the tumour to spread. When Taketo and his group deciphered the route to this corridor, they “knocked them out,” in experimental mice, by looking at cells of colon polyps (growths) that model FAP in humans.

From P1

It is a known fact that NSAIDs affect both COX enzymes. However, COX-2 inhibitors do not usually cause unfavourable effects. Also, because COX-2 is produced early in cancer states, it made sense to Taketo and his group to develop a drug only to block it. In Taketo’s words, “Drugs that inhibit COX-2 are small enough to hit a pocket that exists in COX-2, but not in COX-1. This is the basis of its specificity.” Proof that COX-2 inhibitors get involved early in the development of cancer has now become apparent.

As a matter of fact, the first evidence that COX-2 enzymes were involved in causing DNA damage associated with cancer was provided in a University of Pennsylvania study. The finding offered a new insight into how aspirin, along with diets rich in fruits, grains and vegetables, seemed to decrease the risk of some forms of cancer. Medical scientists who conducted the study also suggested that COX-2 inhibitor drugs may help prevent DNA damage caused by COX-2 enzymes.

Not so simple though, because the timing is critical. COX-2 expression reaches its zenith at a particular stage of the cancer pathogenesis (disease progression). Hence, the timing of cancer treatment to block the enzyme could be just as fundamental. All the same, cancer specialists are optimistic that COX-2 inhibitors that work well on FAP could also help individuals, who suffer from common forms of colon cancer.

In one study, Kelloff and his group of researchers measured the effects of six months of celebrex at low- or high-dose versus placebo on the duodenum in FAP patients. When they monitored the progress, in terms of percentage, the polyp area had decreased substantially (14.5 per cent), in patients given high doses of coxibs, in comparison to the placebo, or dummy pill, group (1.4 per cent). What was remarkable was that in patients, who were severely affected by the disease, celebrex reduced the affected locale by 31 per cent.

COX-2 inhibitors may also be effective on cancers that originate in the small intestine, aside from other types of cancer. Researchers from Hirosaki University School of Medicine in Japan, to illustrate just one study, found COX-2 production in all 26 patients they examined with Helicobacter pylori-associated intestinal-type gastric cancer, except in four patients with scattered gastric cancer.

Besides, they found that COX-2 was predominant in the pre-cancerous (metaplasia) stage. They propose that it would be useful to employ coxib medicines early enough to treat cancer — side-effects notwithstanding — or, use them as a smart cue, or therapeutic tool, to develop new drugs.

(The writer is a wellness physician and author)


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