Cancer Biology: Can Non-Steroidal Anti-Inflammatory Drugs Prevent Cancer - Essay Example

Would an aspirin a day keep cancer away- can non-steroidal anti-inflammatory drugs prevent cancer? The prospect of finding a method of prevention against one of the most expensive and debilitating of all diseases- cancer, in an over-the-counter medication, a non-steroidal anti-inflammatory drug or NSAID, is just too good to be true but researchers over the past 15 years have come up with substantial evidence that this could be true. NSAIDS may be a hurdle to a major mechanism of cancer progression that is inflammation. In the following literature, we will be reviewing how far this theory has been proven through research-based evidence. Non-steroidal inflammatory drugs or NSAIDS are a class of drugs that provide anti-pyretic and analgesic effects at low doses and anti-inflammatory effects at high doses. Aspirin, naproxen and ibuprofen are the most popular members of this group and are used all over the world for several reasons ranging from simple body pain and fevers to daily chemopreventive regimens for patients with cardiovascular diseases. NSAIDS inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2(COX-2) which act as catalysts in the production of thromboxane and prostaglandins. Prostaglandins play a key role in the process of inflammation. While COX-1 is a part of a number of normal physiological processes, COX-2 is specifically used in the process of inflammation. There are two main classes of NSAIDS available in the market, the non-selective COX-1/COX-2 inhibitors, which include aspirin, ibuprofen and naproxen, and the selective COX-2 inhibitors, which include celecoxib. The most common long-term use of NSAIDS is in the case of osteo-arthiritic pain where they not only act as analgesics but also reduce inflammation at joints. The most common adverse side effect of NSAIDS is the increased occurrence of gastric and duodenal ulcers with selective COX-2 inhibitors having lesser gastric effects but an increased suspected risk of myocardial infarction (Bombardier, et al., 2000). COX-2 enzyme is the major link between NSAID use and cancer progression. While the origin of cancer is dependent upon multiple genetic changes which allow uncontrolled multiplication and resistance to apoptotic signals in cancerous cells, the progression of cancer relies upon ancillary processes that are not pathological on their own but are simply the human body’s response to allow repair of injured cells by maintaining homeostasis. One such process is inflammation. Inflammation on its own is an orchestrated effort of human immune system to defend cells against microbes and allow optimum conditions for cellular repair and regeneration. Epidemiological evidence suggests that prolonged inflammatory states can lead to dysplasia which is the first stage in the development of cancer (Nahoum, 2006). As much as 15% of cancers worldwide have been attributed to microbial infections (Kuper, et al., 2000) which may be chronic such as HPV, which causes cervical cancer, or opportunistic such as HHV-8, which causes Kaposi sarcoma. Similarly, states of chronic irritation such as during occupational exposure to asbestos and silica can also lead to development of cancer. Even in tumours which are not caused due to microbial infections, lympho-reticular infiltrates that are very similar to those of inflammation are present during disease progression and it has been noted in patients with Familial Adenomatous Polyposis ( FAP) that consumption of NSAIDS has led to decreased incidences of full-blown intestinal cancers. Thus, there is epidemiological and histopathological evidence along with inflammatory profiles and efficacy results that link cancer to inflammation and this is why the possibility of NSAIDS holding a preventive action against cancers is being explored. When targeting this notion, scientists have come to know that COX-1 is not as important as COX-2 as it plays a larger role with respect to initiation of inflammation and seems to be over-expressed in the lympho-reticular infiltrates of cancerous cells. That is why a greater amount of focus is being given to the inhibitors of the inducible COX-2 rather than the constitutive COX-1 isoform (Wakabayashi, 2000). This is also because the adverse side effects of non-selective cyclooxygenase inhibitors are far severe than COX-2 selective inhibitors and there is considerable concern over long-term use of these drugs. Keeping in mind the same concept, scientists are also looking at COX-2 derived prostaglandin E (2) or PGE (2) in an attempt to come up with safer and more selective drugs that target substances downstream of COX-2 (Cha, et al., 2007) All of this work is being done in the light of epidemiological data that suggests that long-term use of NSAIDS can reduce the risk of several malignancies. 91 epidemiological studies were examined in terms of dose response of relative risks and intake of NSAIDS, primarily aspirin. The dose-response curves showed a risk reduction of 63% for colon cancer, 39% for breast cancer, 36% for lung cancer and 39% for prostate cancer (Harris, et al., 2005). This research also concluded that these effects were observed with at least five years of regular use and risk reduction was higher with longer duration of use. Other malignancies such as those of oesophagus, stomach and ovary showed similar results but to a lesser extent. Thus thorough studies suggest that NSAIDS do have a chemopreventive effect against epithelial malignancies and this effect varies from malignancy to malignancy. Work is now being done on 4 major malignancies which might be prevented by long-term use of NSAIDS such as aspirin and ibuprofen. The highest degree of risk reduction was observed in gastrointestinal cancers, particularly colorectal cancers. Studies have shown a drastic regression in adenomas found in the colon of patients with FAP who have used regular doses of NSAIDS but in higher amounts than the regular cardioprotective doses. NSAIDS are said to cause this effect by inducing cell cycle arrest and a unique mechanism of apoptosis in colon cancer cell lines (DJ, 1998). Although FAP-led colorectal cancers make up only 1% of colorectal cancers in general population, sporadic cancers have also shown a substantial fall in occurrence in patients who have been taking aspirin for 10-15 years. Some of these studies were observational while most were retrospective studies that suggested that the chemoprotective effects of aspirin intake in colorectal cancers were more pronounced at doses of more than 325 mg on alternate days (Marnett, et al., 2002). Similarly, another study done by Vaughan and colleagues on 350 people showed that people who had been taking aspirin regularly in cardioprotective doses showed 68% lesser risk of developing Barrett’s oesophagus (Cerner Multum, 2005). This means that early- stage prevention of oesophageal cancers can be prevented as well. The effect of NSAIDS on COX-2 inhibition may be a very important tool in colorectal cancer prevention but the exact mechanism may not be restricted to that only. Research suggests that there might be an insulin-related pathway for this. The interactions between aspirin and IRS1 and VDR genotypes suggest that there might be more to NSAID’s chemoprotective effect than inhibition of cyclooxygenase (Martha, 2005). Not all works suggest the possibility of this link. Cohort studies suggest lesser reduction in risks of colorectal cancers than case-control studies owing to suspected biases in results. Moreover the dosages that are required in these studies come with their own harmful effects and it is too early to declare NSAIDS to be taken up regularly as chemopreventive agents against gastrointestinal agents (Jolly, et al., 2002). Another cancer that shows decreased occurrence with regular use of NSAIDS is breast cancer. Research suggests that regular use of NSAIDS has a protective effect against breast cancer by inhibiting prostaglandin synthesis. However, these effects were not related to the size of the dose (Weill Cornell Cancer Center, 2009). This stood true for selective as well as non-selective COX inhibitors. This might be possible because PGE2 causes production of aromatase which converts androgens into estrogens which play a key role in development progression of breast cancer (Aspirin Foundation, 2005). In another study, regular users of NSAIDS were compared to non-users and it was found that aspirin users had 13% lesser risk of breast cancer while ibuprofen users had 21% lower risk (Tamkins, 2008). However, not all evidence is suggestive of this hypothesis. A case-control study using database from Scandinavian population suggests that there is no evidence of any risk reduction of breast cancer due to regular NSAID use whether it may be celecoxib, aspirin or ibuprofen (Fenton, et al., 2010). Pulmonary malignancies and their link with NSAID use has been a cause of much speculation and the researches aimed at this proposition have shown that risk reduction is present, more so in smokers than in non-smokers. In a retrospective study which included both men and women and was based on age, gender and pack-years of smoking, it was concluded that the risk was significantly lowered by regular NSAID use, particularly ibuprofen use, and that tobacco carcinogenesis can be prevented by COX-2 blockage (RE, et al., 2002). Some studies suggest more drastic reduction in risk. According to one of those studies, women who had never smoked in their lives and consumed aspirin at least twice on weekly basis had a 50% decrease in risk of lung cancer. The reduction was as high as 62% in smokers (Chen-See, 2012). These and several other works suggest this link to a lesser or greater degree but this topic is also not without debate. Another study conducted in 2007 concluded that the risk reduction was only 5% and that too keeping in mind gaping inaccuracies in the smoking histories of sample candidates. Thus, the study concluded that there was not enough epidemiological evidence to declare NSAID use to be of any significance in risk reduction for lung cancer (Olsen, et al., 2007). Prostate cancer is another malignancy that is being investigated for its link with NSAID use and prevention. In a study conducted at the medical school of Stanford University, scientists who were aiming to study the in vitro effect of calcitriol on prostate cancer coupled it with NSAIDS and found out that not only does this combination suppress prostate cancer growth significantly than anyone drug alone but this effect can be achieved at lower doses of both the drugs (Stanford University Medical Center, 2005). The malignancy that has taken on the role of frontrunner as the major preventable malignancy through NSAID use in recent times is skin cancer. According to a Danish study, regular users of selective as well as non-selective NSAIDS showed a 13% decreased risk of melanoma and a 15% decreased risk of squamous cell carcinoma in comparison to people who took NSAIDS irregularly. The length of time the user had been taking the NSAID as well as the size of the dose had a huge impact on the risk reduction with both having a directly proportional to each other (Alice, 2012). This is precisely where the biggest hurdle of establishing NSAIDS as a chemo-preventive agent for cancer lies. Scientists have found clear molecular evidence of cancer risk reduction by regular NSAID use but the dosages required to achieve this reduction are far too high and side effects of NSAIDS are a major cause of concern at these doses. Gastric bleeding and ulcers along with impaired hepatic and renal function are unavoidable at this point. Therefore, scientists and doctors still are not recommending NSAID use for chemoprevention of cancers and work is continuing to find other facets to this possibility. EXERCISE 1. What is the molecular basis of NSAID activity? ........................................................................................................................................................... 2. What is the molecular basis of NSAID activity against cancer progression? ........................................................................................................................................................... 3. What role does inflammation play in cancer progression? ........................................................................................................................................................... 4. What are the most important malignancies with respect to NSAID chemoprevention? ........................................................................................................................................................... 5. Which microbial or genetic disorders lead to colon cancer? ........................................................................................................................................................... 6. Which NSAID is better for chemoprevention and why? ............................................................................................................................................................ 7. What is the mechanism of chemoprevention of breast cancers by NSAIDS? ............................................................................................................................................... 8. How is NSAID related risk reduction of lung cancer different in smokers and non-smokers? ..................................................................................................................................................... 9. What are the effects of NSAID use on prevention of skin cancer? ........................................................................................................................................................... 10. What is the major drawback of NSAID use as a chemo-preventive agent? ............................................................................................................................................................ Works Cited Alice Park Can Aspirin Help Ward Off Skin Cancer? [Online] // Time Health and Family. - Time corp., 2012. - 2012. - www.time.com. Aspirin Foundation Breast Cancer Prevention [Online] // Aspirin Foundation. - 2005. - 2012. - www.aspirin-foundation.com. 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