Abstract Inflammation is linked to cancer, and many anti-cancer agents are used to treat inflammatory diseases also, such as rheumatoid arthritis.
Moreover, chronic inflammation increases the risk for various cancers, indicating that eliminating inflammation may represent a valid strategy for cancer therapy and prevention. This article explores the relationship between inflammation and cancer with an emphasis on epidemiological evidence, summarizes the current usage of anti-inflammatory agents for cancer prevention and therapy, and describes the mechanisms underlying the anti-cancer effects of anti-inflammatory agents.
Since monotherapy is insufficient for treating cancer generally, the combined usage of anti-inflammatory agents and conventional cancer therapy is also a focal point in discussion. In addition, we also briefly describe future directions that should be explored for anti-cancer anti-inflammatory agents.
Inflammation and Cancer It has been recognized that infections and inflammation are related to cancer long, and strong correlations between the existence of inflammation and the development of pre-cancerous lesions at various anatomic sites have been established. Thus, the existence of inflammation appears to induce or facilitate carcinogenesis. That inflammation may result in the initiation of cancer is reasonable considering that chronic inflammation is characterized by infiltration of mononuclear immune cells including macrophages, lymphocytes, and plasma cellstissue destruction, fibrosis, and increased angiogenesis 9 Increased genomic damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways, inhibition of apoptosis, and the promotion of angiogenesis and invasion are also associated with chronic inflammation All of these processes have been implicated in the initiation and progression of cancers.
During chronic inflammation, pro-inflammatory molecules, such as cytokines, inducible nitric oxide synthase iNOSreactive oxygen species ROSand NF-kB are upregulated Together, these processes provide a favorable microenvironment for the exponential growth of malignant cells. Thus, inflammation might provide both the key mutations and the proper environment to foster tumor growth.
As a tumor develops, it expresses phenotypes similar to inflammatory cells For example, numerous cancer cells express chemokines and cytokines and their receptors. These molecular mediators and their respective receptors have a significant impact on angiogenesis, cell migration, and metastasis 14 Surprisingly, the expression level of IL-8, an important regulator of neutrophil chemotaxis and activation, and an activator of NF-kB, corresponded with estrogen receptor status negatively; the mediator was more abundant in high-grade tumors than low-grade tumors also, and was increased in tumors that exhibited high macrophage content and increased vascularization.
Its expression corresponded to B lymphocyte, T lymphocyte, and macrophage infiltration, and was found to correlate with the overall existence of inflammatory cell elements Additionally, the observed levels of AP-1 activator protein-1a transcriptional target of NF-kB and known regulator of numerous inflammatory cytokines, correlated with the expression levels of many of the examined cytokines.
Targeting Inflammation for Cancer Therapy Given its myriad pro-tumor effects, inflammation has become a target for cancer therapy and prevention. More than two decades ago, it was demonstrated that NSAIDs non-steroidal anti-inflammatory drugs have anti-colon cancer effects 21 Other clinical trials have indicated that long-term usage of aspirin or other NSAIDs decreases the incidence of colorectal, esophageal, breast, bladder and lung cancers Nevertheless, given that their toxicity is modest compared to conventional chemotherapeutic agents, various anti-inflammatory agents are being investigated for cancer therapy and prevention still.
Many anti-inflammatory agents, including the NSAIDs, can alter the tumors themselves or the tumor microenvironment, potentially decreasing migration 26increasing apoptosis 27and increasing sensitivity to other therapies 28 ; thus, the agents have immense promise against cancer still. The remainder of this review will concentrate on the current status, mechanisms of action, and future directions for the use of anti-inflammatory agents for cancer therapy. Current Status of Anti-Inflammatory Agents for Cancer Dysregulated inflammation plays a major role in chronic illnesses, including diabetes, cardiovascular disease, arthritis, psoriasis, and cancer As a total result, there are numerous FDA-approved anti-inflammatory agents for these indications.
Although they were designed to decrease or prevent inflammation, many of these agents exhibit other properties such as anti-emetic, anti-thrombotic 30anti-angiogenic 31anti-proliferative, and pro-apoptotic activities 32making them potential applicants for cancer therapy or prevention. NSAIDs Epidemiological data recommend that the incidence of breast, colorectal, and lung cancers is inversely related to the use of aspirin and nonsteroidal anti-inflammatory drugs Randomized trials have demonstrated that aspirin can reduce the short-term risk of colon adenomas in patients with a prior history of adenomas Another study demonstrated that the incidence and mortality from lung cancer for patients taking aspirin was considerably lower for non-smokers and former smokers than those who did not take aspirin However, other studies, such as one in breast cancer patients, did not demonstrate any reduction in cancer risk for patients taking aspirin for up to 10 years follow-up Sulindac, another NSAID, has also been proven to decrease the recurrence and polyp number in FAP familial adenomatous polyposis patients 38 and result in the regression of existing adenomas Other NSAIDs, including piroxicam and ibuprofen, have also been proven to decrease the risk of developing cancers 40 Thus, there appears to be a significant correlation between NSAID use and decreased incidence of recurrent and primary cancers, and decreased mortality, although the effects vary by dose, duration of exposure, cancer type, and the duration of follow-up.
All of these agents have been approved by the FDA for different indications, and could be added to cancer therapy or prevention regimens readily. Clinical studies involving patients with FAP demonstrated that celecoxib Early, a specific COX-2 inhibitor, induced significant regression of existing adenomas These findings led to the accelerated FDA approval of celecoxib for adjuvant therapy in the treatment of familial adenomatous polyposis in Studies have also indicated that celecoxib may have activity against other cancers, such as ovarian cancer, as well However, the usage of celecoxib and other NSAIDs for cancer prevention and therapy remains controversial, with many clinical studies indicating that the compounds do not have significant beneficial effects for patients.
Moreover, the relative side effects of the NSAIDs, ranging from moderate GI toxicity to cardiotoxicity, limit enthusiasm for their use, for cancer prevention especially. As a total result of their cardiotoxicity, the majority of the COX-2 specific agents have been withdrawn from the market. Given their toxicity and the controversy surrounding their cancer therapeutic and preventive affects, it is unlikely that COX-2 inhibitors shall play a major role in cancer prevention or as monotherapy for cancer, however, they might represent effective treatments when used as adjuvants with other therapeutic approaches.
Corticosteroids The corticosteroids, most commonly used to prevent or decrease the relative side effects of chemotherapy and radiation, have also proven anti-cancer activity when used or in mixture with chemotherapeutic agents alone.
Our studies have demonstrated that pre-treatment with dexamethasone can enhance the effects of conventional therapies against animal models of glioma, as well as breast, lung and colon cancers 47 A recent study in cell lines and a xenograft model demonstrated that dexamethasone treatment results in significant growth inhibition of renal cell carcinoma It has also been demonstrated that dexamethasone can prevent the growth of estrogen-dependent breast cancer by antagonizing estrogen sulfotransferase Other glucocorticoids, including prednisone and hydrocortisone, have also been proven to decrease the growth of cancer cells in culture and also to decrease the growth of xenograft tumors in vivo 51 Thus, anti-inflammatory agents appear to have promise for the treatment or prevention of various human cancers.
These agents, the NSAIDs particularly, have been documented to decrease migration 26increase apoptosis 2753and decrease angiogenesis 5455 of tumors. These effects, and epidemiological evidence of decreased cancer aggressiveness and incidence, prompted the numerous investigations of the potential of anti-inflammatory agents for cancer therapy and prevention.
While the results so far have been inconclusive, it cannot be denied that these compounds might represent novel, less toxic, agents for cancer therapy. However, like the majority of the agents used in the clinic currently, the anti-inflammatory compounds will likely need to be used as part of a mixture regimen in order to achieve successful eradication of established tumors.
Mechanisms of Anti-Cancer Action of Anti-Inflammatory Agents There is evidence that anti-inflammatory agents are effective adjuvants for conventional therapies 28 Since monotherapy is typically insufficient to completely eradicate cancer, combination therapy is administered.
A number of both clinical and pre-clinical studies recommend that the combined usage of anti-inflammatory agents and conventional therapies may improve patient prognosis. Although the underlying mechanisms of action for the effects of anti-inflammatory agents as adjuvants are not fully demonstrated, three primary modes of action have been proposed: chemoprotection, alterations in metabolism or pharmacokinetics, and chemosensitization.
Chemoprotection by anti-inflammatory agents There are a sizable number of adverse effects associated with the various clinically used anti-cancer agents. The majority of agents target proliferating cells, resulting in toxicity to both the tumor and various host tissues, the gastrointestinal tract and bone marrow primarily.
Other toxicities arise because of this of accumulation of the agent in a particular anatomic region e. These relative side effects limit the dose of agent that can be given, and reduce patient quality of life greatly. The ability to prevent or ameliorate these side effects would both enhance the therapeutic response and improve patient quality of life. There have been several studies which have demonstrated that administration of anti-inflammatory agents can decrease the toxicity of conventional chemotherapeutic agents.
For example, combining celecoxib with docetaxel decreased hematologic toxicity in patients with refractory metastatic prostate cancer, even though it only slightly decreased the pain index for patients A trial investigating the mixture of capecitabine and celecoxib for patients with metastatic breast cancer indicated that the addition of the COX-2 inhibitor decreased the incidence of capecitabine-associated diarrhea and hand-foot syndrome The recently completed GECO Gemcitabine-Coxib study was designed to evaluate the addition of rofecoxib to first-line chemotherapy regimens in patients with advanced non-small cell lung carcinoma NSCLC.
Despite the withdrawal of rofecoxib and the consequent cessation of the treatment arm, patients getting adjuvant rofecoxib therapy exhibited higher response rates.
Additionally, patients who had undergone at least 3 months of rofecoxib treatment experienced improved quality of life, measured by decreased fatigue, weight loss, pain, and analgesic consumption Our own studies have focused on the anti-inflammatory glucocorticoid, dexamethasone.
Dexamethasone has been used as an anti-emetic for cancer patients for many years, but has more been examined for potential chemoprotective and therapeutic effects recently. In our studies, we observed that dexamethasone decreased the hematotoxicity of gemcitabine and carboplatin in both CD-1 mice and human NSCLC patients in a dose- and schedule-dependent manner 60 A study in advanced colorectal cancer patients demonstrated that administration of a different glucocorticoid, budesonide, led to a trend toward decreased incidence and duration of diarrhea in patients getting irinotecan, as well as a diminished need for loperamide rescue Other NSAIDS, aspirin in particular, may also prove to be beneficial as anti-thrombotic agents if administered in mixture with chemotherapeutic modalities.
These effects were attributed to both COX inhibition and a decrease in the expression and activity of matrix metalloproteinases MMPs 3 and 9 Glucocorticoids, including dexamethasone, have also been proven to stabilize the blood-brain barrier, and are used to treat cerebral edema frequently. Dexamethasone may exert its effect by decreasing VEGF and increasing angiopoietin-1 These studies indicate that the use of anti-inflammatory agents may prevent or inhibit many of the dose-limiting toxicities of several of the most commonly used anti-neoplastic agents.
Anecdotal evidence suggests that other agents might have similar effects, implying that mixture therapy with conventional chemotherapeutic agents and anti-inflammatory agents is an under-investigated area that may yield significant improvements in patient care.
Alterations in pharmacokinetics or metabolism One of the mechanisms accountable for the chemoprotection induced by anti-inflammatory agents is that their administration can change the pharmacokinetics and pharmacodynamics of other therapeutic agents. For example, dexamethasone was proven to protect mice from hematotoxicity in a dose- and schedule-dependent manner. It was demonstrated that the drug altered the pharmacokinetics of carboplatin, gemcitabine and doxorubicin in both CD-1 mice and in a variety of mouse xenograft cancer models 4748 More importantly, when animals were pre-treated with dexamethasone, the AUCs of the chemotherapeutic agents in the tumor were increased, while the AUCs in the bone marrow and spleen decreased Similar effects were observed when dexamethasone was combined with adriamycin in a syngeneic model of mammary cancer Thus, administration of the glucocorticoid can alter the pharmacokinetics of chemotherapeutic agents to decrease their toxicity and increase their activity in the tumor.
Even when the anti-inflammatory agents do not affect the pharmacokinetics of the chemotherapeutic agent, they might alter its metabolism, leading to distinctions in the concentration, half-life, and clearance of the active metabolite, altering the toxicity and efficacy of the agent s thus. For example, several agents, including rofecoxib and mefenamic acid, are potent inhibitors of CYP1A2 Dexamethasone is an inducer of CYP2D6, while celecoxib inhibits the activity of the enzyme It is possible that by affecting CYP2D6 activity, dexamethasone or celecoxib may alter the efficacy of tamoxifen which is metabolized by CYP2D6 treatment for stopping breast cancer recurrence.
Other mechanisms by which the anti-inflammatory agents can alter metabolism of chemotherapeutic agents are also possible.
Another factor influencing the amount of drug reaching the tumor is the tumor interstitial fluid pressure IFP. Most tumors have high IFP, most likely resulting from abnormal lymph or vasculature vessels, or fibrosis of the surrounding stroma This high pressure acts as a barrier to drug delivery to the tumor from the circulation, stopping therapeutic agents the majority of which have relatively high molecular weights from entering tumor cells Various studies have demonstrated that high IFP correlates with a worse prognosis and decreased response to therapy In our studies, we observed an increased uptake of chemotherapeutic agents by xenograft tumors following pre-treatment with dexamethasone This effect may have been due to the change in tumor IFP Another study indicated that there was a trend toward reduced tumor IFP in patients treated with celecoxib Thus, changes in the metabolism or distribution of chemotherapeutic agents can be induced by prior or co-administration of anti-inflammatory agents.
While these changes can be deleterious under many conditions, it is also possible as in the case of dexamethasone to use these changes to protect normal tissues from toxicity or to raise the efficacy of a particular chemotherapeutic agent.
Special care must be taken for studies that target distinctions in metabolism to make sure that all patients have metabolic enzymes that function at normal levels.