[NAMJS. 2010;3(3):160-166.] PDF Full Text

Jing Liu, MD, PhD, Jianbo Wan, PhD, Cheng Wei He, PhD

Abstract
Chemotherapeutic drugs have been conventionally used for the cancer treatments, but the efficacy of the therapy remains problematic. It has been strongly suggested that the anti-inflammatory drugs, such as COX-2 inhibitors, may enhance the anti-cancer efficacy of chemotherapeutic drugs and reduce the chemo-resistance. Herein, the rational of the use of anti-inflammatory agents in the cancer treatment is summarized. One of the most important inflammatory processes occurs during metabolism of the eicosanoids, which involved arachidonic acid (AA), cyclooxygenase 2 (COX-2), prostaglandins (PGs) and leukotriens (LTs). As the results of excessive up-regulation of COX-2 and production of PGE2, for example, the harmful inflammation may promote the cancer development. The inflammation also involve in the drug resistance of the chemotherapy. In fact, many in vitro and in vivo studies have showed the positive potentials using COX-2 induce serious damages to stomach, kidney and heart, which have restricted the clinical uses of these drugs. For inhibitors in the cancer treatment. However, the regular

anti-inflammatory agents, mainly COX-2 inhibitors, may the reason, growing numbers of studied have targeted on the natural anti-inflammatory substances and expected to find the effective adjuvant to the chemotherapeutic drugs without the safety concern. On the other hand, the counteraction between the chemotherapy and natural substances has been concerned clinically. Therefore, the natural substances, which were studied for their anti-inflammation effects, are listed. The potential enhancing effects of some of the national anti-inflammatory agents on chemotherapeutic agents are reviewed. A guideline for clinical use of these natural agents with chemotherapy is suggested although limited clinical trial data available. In conclusion, the existing evidences suggest that some natural anti-inflammatory substances have potential to be used as adjuvant agents to enhance the efficacy and reduce the resistance of the chemotherapy. But more research and clinical trials are needed to support the suggestions.

Introduction
Growing evidence shows that inflammation not only contributes to cancer development, but also affects chemotherapy efficacy and resistance. It has been well documented that cyclooxygenase 2 (COX-2) plays an important role in the inflammatory pathway.1-3 Intensive studies have targeted anti-inflammatory agents, particularly COX-2 inhibitors, as new adjuvant agents in chemotherapy.4-6 Although numerous studies have suggested a role of COX-2 inhibitors in chemoprevention, serious side effects involving the heart, kidneys and stomach have hindered their clinical application.7,8 Therefore, mounting interest has shifted to investigating natural substances that possess anti-inflammation and COX-2 inhibiting effects but less toxicity and side effects. Moreover, these natural substances may also convey multiple beneficial pharmacological effects, including immune function enhancement and cancer growth inhibition.

COX-2, Inflammation, and Cancer
Normal inflammation is a necessary protective response to harmful stimuli to the body, such as infectious pathogens and toxic chemicals. However, prolonged or excessive inflammation is believed to be a possible contributor to angiogenesis and cancer development.9-12 One of the most important inflammatory processes occurs during metabolism of the eicosanoids, which include prostaglandins (PGs) and leukotriens (LTs). Arachidonic acid (AA) is the precursor of eicosanoids on cell membranes and is enzymatically metabolized to PGs and LTs by cycloxygenase (COX) and lipoxygenase respectively. Multiple molecules or pro-inflammatory factors in the COX-2 pathway are involved in the inflammation process (Figure 1). Some of these factors play important roles in the formation, development and metastasis of cancer.1 A new generation of pharmaceutical anti-cancer drugs has been developed to target the molecules which are involved in the COX-2 pathway, including PGE-2, tyrosine kinase, growth factors and angiogenesis.3,10,13 COX-2 plays a central role in controlling and modulating the speed of the biochemical cascade in the eicosanoid pathway, particularly in the production of PGE-2.14-20 PGE-2, one of the downstream products of COX-2, is a key stimulator of inflammation, cell migration and proliferation, while inhibiting cell death. Pro-inflammatory stimulators result in COX-2 and PGE-2 over-production, and cancer may occur as a result of inflammation.21,22 A number of clinical investigations have demonstrated high COX-2 activity in patients with a variety of cancers, including colorectal, gastric, breast, non-small cell lung, ovarian, hepatocellular, pancreatic, bladder, skin cancers, and particularly, 80-90% of colon cancer patients.23-28 Epidemiologic studies suggest that non-steroid anti-inflammatory drugs (NSAIDs), including aspirin and indomethacin, have significant preventative effects on certain types of cancer.29,30 The activity of COX-2 can be stimulated by a variety of interior and exterior factors. The external COX-2 stimulators include Epstein-Barr virus, Streptococcus pneumoniae, phorbol ester and desferrioxamine. These factors may trigger AA release and the expression of COX-2 enzyme.31 In epithelial colon cancer, the epidermal growth factor receptor (EGFr) activates tyrosine kinase resulting in excessive up-regulation of COX-2 expression. Consequently, this process results in up-regulation of PGE2, which is believed to be a possible contributor to tumor metastasis.32 Other studies suggest that COX-2 is sensitive to hypoxia and oxygen-derived free radical injury, showing elevated levels in hypoxic conditions.33-35 In response to pro-inflammatory stimuli, phagocytic cells of the immune system require rapid consumption of O2 and comprise a major source of free radicals in the body. The lipid bilayer of the cell membrane is easily damaged by exposure to excessive levels of free radicals. As a result, AA on the cell membrane is released into cytosol and triggers the eicosanoid cascade. COX-2 up-regulators also include NO, epithelial growth factor, lipopolysacharide, omega-6 fatty acids, IL-4, IL-1, IL-6, TGF- and TNF-.36-39 Conversely, chemicals that inhibit COX-2 function also exist in our body and include substances such as omega-3 fatty acids, melatonin, pyruvate and IFN-.40

Thus it is reasonable to postulate that many natural antioxidants may contribute to cancer prevention by modulating COX-2 activity and inflammation.

Benefits and Limitations of COX-2 Inhibitors on Chemotherapy
A number of NSAIDs and specific COX-2 inhibitors have been investigated for their anti-cancer properties and their adjuvant roles in chemotherapy. Celecoxib, aspirin and indomethacin are among the most frequently reported agents. Recent evidence indicates that potential benefits may be achieved by combining COX-2 inhibitors with certain chemotherapeutic agents. A clinical study revealed that Celecoxib enhanced colorectal tumor response to capecitabine and increased the median time to tumor progression (6 vs. 3 months, P = 0.002) as compared to capecitabine alone.41 In addition to increasing efficacy Celecoxib may also reduce the side effects of chemotherapy in colon cancer.42 COX-2-induced anti-apoptosis has been shown to be mediated by the release of PGE2 and subsequent cAMP-dependent cellular inhibitors of apoptosis protein induction. Correspondently, NSAIDs may disrupt this pathological apoptotic process, thereby enhancing the efficacy of chemotherapy for colon cancer.43
Bcl-2, an oncogene, confers resistance to multiple chemotherapeutic treatments in a variety of cancers, including breast, lung, prostate cancers and leukemia. Down regulation of Bcl-2 may improve the cytotoxicity of chemotherapeutic agents in several cancer cell lines.44,45 Selective COX-2 inhibitors SC-58125 and NS-398 can down regulate Bcl-2 and promote apoptosis in LNCaP cells, an epithelial cell line derived from a human prostate carcinoma.46 Compared to taking indomethacin, adriamycin or cisplatin administrated alone, which showed limited effects in inhibiting the growth of the C20 tumors, a combination of two of these medications demonstrated synergistic effects. The effects accompanied with the expression of monocyte chemotactant protein-1 (MCP-1).47 Interestingly, NSAID and COX-2 specific inhibitors have shown several COX-2 independent properties, suggesting that multiple COX-2 independent targets should also be investigated in future studies.14,20

Chemotherapeutic drug resistance is a constant challenge in clinical cancer treatment, particularly for metastatic carcinoma. Inflammation and pro-inflammatory cytokines are strong intrinsic factors promoting multiple drug resistance (MDR).48 A number of studies have demonstrated that chemotherapy may induce the activities of COX-2 and inflammation stimulating the P-Glycoprotein involved in MDR, which transports drug out of the cancer cells. COX-2 inhibitors, particularly celecoxib, counteract MDR.49,50

It is not surprising that tumors may selectively respond to different combinations of chemotherapeutic agents and COX-2 inhibitors. Kobayashi et al., tested different combinations of chemotherapeutic agents including Adriamycin, 5-fluorouracil, cisplatin and vincristine for their efficacies on the growth of human pulmonary adenocarcinoma cells. The anti-inflammatory agents examined included aspirin, ibuprofen, sulindac, and indomethacin. The result showed that the combination of indomethacin and vincristine produced the most effective anticancer effects, compared with the other 10 chemotherapeutic agents and 5 anti-inflammatory agent combinations.51 Their results also suggest that individual natural anti-COX-2 agents need should be tested specifically with each chemotherapeutic agent on tumor targets.

The side effects of the chemical COX-2 inhibitors have restricted their clinical usage on cancer prevention and treatment. COX-2 inhibitors showed many serious complications in altering the normal body’s homeostasis.7 For example, coxibs, including celecoxib, rofecoxib and valdecoxib, increase atherosclerosis, thrombogenesis, cardiovascular disease and even cardiac attack by inhibiting the generation of prostacyclin (PGI2) and mitochondrial oxidative phosphorylation.52 COX-2 inhibitors may also cause a marked decline in glomerular filtration rate and lead to acute renal failure.8 Therefore, natural anti-inflammatory agents with COX-2 inhibitory effects have become potential substitutes because of their excellent safety record.

Chemoprevention with Natural Anti-Inflammatory Substances
A growing number of natural substances have been discovered with anti-inflammatory and COX-2 inhibiting effects. The potential of these natural anti-inflammatory agents on chemoprevention has been under investigation worldwide. A long list of herbs has been described with anti-COX-2 effects. These substances are used as either food supplements such as green tea, ginger, grape seeds and holy basil, or regarded as therapeutic herbs such as salvia miltiorrhiza bunge, fevervew, nettle leaf, oregano, rosemary, giardina C. butyrate, stylopine, chelidonium majus, ginsenoside Rh, scutellaria bacalensis, phellodendron amurense, cyanidin, carthamus tinctorius, carthamus tinctorius L. seed, anthocyanidin and willow bark.32, 53-60

Turmeric or curcuma longa has been used in China and India as a food spice and anti-inflammatory medicine for generations. Since the anti-COX-2 effect of turmeric was discovered by scientists at Vanderbilt University, Cornell University and University of Leicester in England, a growing body of reports have confirmed that turmeric is a strong anti-inflammation agent. The active anti-inflammation component is curcumin, which is about 50% as effective as cortisone. A number of publications have reported the anti-cancer effects of turmeric and encouraging synergistic effect with chemotherapy.61-63

A number of studies on coptis (coptis Chinensis, Huang Lian), a common herb in beberidaceae, has also drawn interest. Coptis is a commonly used anti-inflammatory herb in traditional Chinese medicine. Modern medical research reveals that both coptis and berberine, the major alkaloid in Coptis, possess multiple pharmacological properties, including anti-inflammation, anti-infection and anti-cancer effects.64 The mechanism of the anti-inflammation effect may be related to COX-2 inhibition and the anti-oxidant properties of berberine.65-68 Several investigations have demonstrated the anti-cancer potential of coptis and berberine in in vitro and in vivo studies.68-70 Studies conducted in our lab and by others have shown coptis and berberine-induced apoptosis in breast cancer cells.71,72

The role of omega-3 on inflammation and cancer modulation has been neglected until the last decade. Omega-3 can effectively inhibit COX mediated AA metabolism and PGE-2 inducible cancer.73,74 Conversely, a high omega-6, low omega-3 diet may promote cancer.75 The omega-3 enriched plants, such as flaxseed and Perilla frutescens seed have also been under investigations for their supplemental benefits in cancer treatment.76, 77

So far, no natural compounds are effective enough to replace current chemotherapeutic drugs. However, the combination of chemotherapeutic drugs with natural anti-inflammatory agents demonstrates encouraging potential. This integrated cancer treatment approach has been adopted in China for at least 40 years. However, these herbal compounds usually contain several herbs with different functions in addition to anti-inflammatory compounds. So far, most of the investigations on chemoprevention with natural COX-2 agents have been restricted to the laboratory. The role of natural anti-inflammatory agents in cancer treatment has not been well established. Curcumin was reported to have synergistic effects in chemoprevention,78 although several earlier reports indicated the opposite.79,80,81 A possible explanation for these disparate results could be that most natural compounds that inhibit COX-2 are antioxidants as well, and there is much debate regarding whether antioxidants counteract the efficacy of chemotherapy. It is recognized that one of the important mechanisms by which chemotherapy induces apoptosis is the generation of intracellular reactive oxygen species (ROS).82 Antioxidants might counteract chemotherapy this way. Conversely, several recent studies support the thesis that antioxidants can enhance the anti-cancer effects of chemotherapy.83,84,85 Block KI analyzed the results of antioxidant applications during chemotherapies from selected 19 trials of 845 articles. Only randomized, controlled clinical trials that reported survival and/or tumor response were included in the final tally. Antioxidants evaluated included glutathione, melatonin, vitamin A, vitamin C, N-acetylcysteine, vitamin E, ellagic acid and antioxidant mixture. None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls; however, lack of adequate statistical power was a consistent limitation.86

To avoid the worry that the herbs may counteract with the efficacy of the chemotherapy, we suggest that natural supplements may be taken after chemotherapeutic agents no longer be active in the body, which could range from hours to a few days. The information of pharmacodynamics of the agents, such as bioavailability, half-life time, maximum concentration in the plasma, should be searched before natural supplements are administered. In this way, natural anti-inflammatory agents or antioxidants can yield their benefits without the concern of interaction with chemotherapy. On the other hand, we assume that unhealthy level of ROS and free radicals should be reduced during the intervals of chemotherapies, so as to avoid the continuous damage to the immune function and general homeostasis of the body. Furthermore, the natural agents may eliminate the inflammation produced from chemotherapy which may result in chemo-resistance.87,88

Prospective Research
Recent data reveals clues that anti-inflammatory drugs, which can interfere with multiple pro-inflammatory targets on the eicosanoid cascade, showed more therapeutic potential for cancer treatment. For example, a combined EGFR and COX-2 inhibitor treatment has the potential to be a new therapy for non-small cell lung cancer.14 Berberine not only reduces production of PGE2 but also enhances IL-12 and INF-β, which could explain its effect on apoptosis of ER positive breast cancer cells.72 Recently, we have discovered that berberine and coptis significantly improved the anticancer effects of estrogen receptor antagonists, tamoxifen and fulvestrant on MCF-7 breast cancer cells. The molecular mechanism underlying such action of these herbs may be the results of the down-regulation of EGFR, HER2 and bcl-2, and up-regulation of IFN-β and p21.89 Many in vitro and in vivo studies show that Celecoxib possesses the most potent synergistic chemotherapy effects. Celecoxib can inhibit COX-2 generation, while inhibiting IL-8, TNF-, NF-B and apoptotic-related proteins.15 The above reports suggest that an experimental model for multiple inflammation-cancer molecular targets should be established for evaluating the role of natural anti-inflammatory agents on cancer treatment.

What would be the real advantage of studying on the natural anti-inflammatory agents for the cancer treatment? A proposed optimal anti-inflammatory agent should be a multiple targeted inflammatory signal pathway modulator: a. properly down-regulating the excessive the gene expressions on the eicosanoid signal pathway, including COX-2, PGE-2, angiogenesis, tyrosine kinas and IL-1; b. promote INF-and IL-18 at the same time. To formulate such an natural COX-2 inhibitor “cocktail” seems much easier than to formulate a chemical compound for the same purpose, considering less side effect and toxicity of the most natural compounds and enriched clinical experiences in using the compound herbal formulas.90

More investigations are needed to avoid the unexpected toxicity and possible lower therapeutic efficacy of chemotherapy resulting from herb-chemotherapeutic drug interactions. Almost all herb-chemotherapeutic drug interactions occur at the pharmacokinetic level, which involves cytochrome P450 (CYP) metabolizing enzymes or phase II enzymes. Some investigators have reported the effects of herbs on the specific CYP or multiple CYP enzymes.91,92 Based on these studies, a preliminary evaluation for herb-chemotherapeutic agent interaction could be derived to guide the clinical uses of the herbs in combination with chemotherapy before considering the clinical trial.
In summary, the application of natural anti-inflammatory agents in chemotherapy may open a new field for the treatment of cancer. However, more studies, especial well-designed clinical trials in using the anti-inflammatory natural substances with chemotherapy are needed to define the optimal integrated approach for various cancer types.

Jing Liu, MD, PhD, Jianbo Wan, PhD, Cheng Wei He, PhD
Department of Medicine
Massachusetts General Hospital
and Harvard Medical School
Boston, Massachusetts 02119, USA

(*Corresponding author)
Jing Liu, MD, PhD
Massachusetts General Hospital,
Room 4431, Building 149 13th Street
Charlestown, MA 02129, USA.
Tel: 781-290-9042 Fax: 781-642-7824
Email: jliuO@partners.org

Jianbo Wan, PhD
Tel: 339-293-9093 Fax: 617-726-6144
Email: jwan1@partners.org
Chengwei He, PhD
Tel: 617-726-6492 Fax: 617-726-6144
Email: che3@partners.org

References
1. Park GY, Christman JW. Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol. 2006;290(5):L797-805.
2. Wallace JL. COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation. Scientific World J. 2006; 25(6):577-588.
3. Murahami M, Kudo I. Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr Pharm Des. 2006;12(8):943-954.
4. Tkacz VL, Tohnya TM, Figg WD. Cyclooxygenase-2 and Angiogenesis in Prostate Cancer. Cancer Biol Ther. 2005;4(8):813-814.
5. Brueggemeier RW, Diaz-Cruz ES. Relationship between aromatase and Cyclooxygenase in breast cancer: potential for new therapeutic approaches. Minerva Endocrinol. 2006;31(1):13-26.
6. Wendum D, Masliah J, Trugnan G, et al. Cyclooxygenase-2 and its role in colorectal cancer development. Virchows Arch. 2004; 445(4):327-333.
7. Nakanishi Y, Kamijo R, Takizawa K, et al. Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines. Eur J Cancer. 2001;37(12):1570-1578.
8. Sharma JN, Jawad NM. Adverse effects of COX-2 inhibitors. Scientific World Journal. 2005; 18;5:629-645
9. Woywodt A, Schwarz A, Mengel M, et al. Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol. 2001;28(9):2133-2135.
10. Smith CJ, Perfetti TA, King JA. Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhal Toxicol. 2006;18(9):667-677.
11. Ruegg C, Zaric J, Stupp R. Non steroidal anti-inflammatory drugs and COX-2 inhibitors as anti-cancer therapeutics: hypes, hopes and reality. Ann Med. 2003;35(7):476-487.
12. Farazi PA, Zeisberg M, Glickman J, et al. Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice. Cancer Res. 2006;66(13):6622-6627.
13. Wang X, Deavers M, Patenia R, et al. Monocyte/macrophage and T-cell infiltrates in peritoneum of patients with ovarian cancer or benign pelvic disease. J Transl Med. 2006;4(1):30.
14. Richardson CM, Sharma RA, Cox G, O’Byrne KJ. Epidermal growth factor receptors and cyclooxyenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy. Lung Cancer. 2003;39(1):1-13.
15. Konturek PC, Rembiasz K, Burnat G, et al. Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. Dig Dis Sci. 2006;51(4):779-787.
16. Abelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 2005;68(2):317-329.
17. Koehne CH, Dubois RN. COX-2 inhibition and colorectal cancer. Semin Oncol. 2004;31(2 Suppl 7):12-21.
18. Takahashi T, Baba M, Nishino H, Okuyama T. Cyclooxygenase-2 plays a suppressive role for induction of apoptosis in isoliquiritigenin-treated mouse colon cancer cells. Cancer Lett. 2006;231(2):319-325.
19. Tong X, Yin L, Joshi S, Rosenberg DW, Giardina C. Cyclooxygenase-2 regulation in colon cancer cells: modulation of RNA polymerase II elongation by histone deacetylase inhibitors. J Biol Chem. 2005;280(16):15503-15509.
20. Wagner M, Loos J, Weksler N, et al. Resistance of prostate cancer cell lines to COX-2 inhibitor treatment. Biochem Biophys Res Commun. 2005;332(3):800-807.
21. Calatayud S, Warner TD, Breese EJ, Mitchell JA. Relationship between endogenous colony stimulating factors and apoptosis in human colon cancer cells: role of cyclo-oxygenase inhibitors. Br Pharmacol. 2001;134(6):1237-1244.
22. Backlund MG, Mann JR, Dubois RN. Mechanisms for the prevention of gastrointestinal cancer: the role of prostaglandin E2. Oncology. 2005;69 (Suppl 1):28-32.
23. Müller-Decker K, Fürstenberger G. The cyclooxygenase-2-mediated prostaglandin signaling is causally related to epithelial carcinogenesis. Mol Carcinog. 2007;46(8):705-710.
24. Sheehan KM, Sheahan K, O’Donoghue DP, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA. 1999;282(13):1254-1257
25. Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control. 2002;9(2 Suppl):28-35.
26. Khuri FR, Wu H, Lee JJ, et al. Cyclooxygenase-2 over expression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res. 2001;7(4):861-867.
27. Shiota G, Okubo M, Noumi T, et al. Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology. 1999;46(25):407-412.
28. Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ. Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr Relat Cancer. 2001;8(2):97-114.
29. Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signaling and apoptosis. Br J Cancer. 2004;91(2):381-388.
30. De Groot DJ, De Vries EG, Groen HJ, De Jong S. Non-steroidal anti-inflammatory drugs to potentiate chemotherapy effects: from lab to clinic. Crit Rev Oncol Hematol. 2007;61(1):52-69.
31. Kaul R, Verma SC, Murakami M, Lan K, Choudhuri T, Robertson ES. Epstein-Barr virus protein can upregulate cyclo-oxygenase-2 expression through association with the suppressor of metastasis Nm23-H1. J Virol. 2006;80(3):1321-1331.
32. Sandberg T, Ehinger A, Casslen B. Paracrine stimulation of capillary endothelial cell migration by endometrial tissue involves epidermal growth factor and is mediated via up-regulation of the urokinase plasminogen activator receptor. J Clin Endocrinol Metab. 2001; 86(4):1724-1730.
33. Csiki I, Yanagisawa K, Haruki N, et al. Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1alpha in non-small cell lung cancer. Cancer Res. 2006;66(1):143-150.
34. Uenoyama Y, Seno H, Fukuda A, et al. Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway. Oncogene. 2006;25(23):3277-3285.
35. Woo KJ, Lee TJ, Park JW, Kwon TK. Desferrioxamine, an iron chelator, enhances HIF-1 alpha accumulation via Cyclooxygenase-2 signaling pathway. Biochem Biophys Res Commun. 2006;343(1):8-14.
36. Cianchi F, Cortesini C, Fantappiè O, et al. Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin Cancer Res. 2004;10(8):2694-2704.
37. Chen YC, Shen SC, Chen LG, et al. Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem Pharmacol. 2001;61(11):1417-1427.
38. Hughes-Fulford M, Li CF, Boonyaratanakornkit J, Sayyah S. Arachidonic acid activates phosphatidylinositol 3-kinase signaling and induces gene expression in prostate cancer. Cancer Res. 2006; 66(3):1427-1433.
39. Park YG, Kang SK, Kim WJ, et al. Effects of TGF-beta, TNF-alpha, IL-beta and IL-6 alone or in combination, and tyrosine kinase inhibitor on cyclooxygenase expression, prostaglandin E2 production and bone resorption in mouse calvarial bone cells. Int J Biochem Cell Biol. 2004;36(11):2270-2280.
40. Jang SI, Kim BH, Lee WY, et al. Stylopine from Chelidonium majus inhibits LPS-induced inflammatory mediators in RAW 264.7 cells. Arch Pharm Res. 2004; 27(9):923-929.
41. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park). 2002;16(12 Suppl No 14):31-37.
42. Swamy MV, Cooma I, Patlolla JM, et al. Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid: novel strategies for colon cancer prevention and treatment. Mol Cancer Ther. 2004; 3(2):215-221.
43. Nishihara H, Kizaka-Kondoh S, Insel PA, Eckmann L. Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2. Proc Natl Acad Sci U S A. 2003; 100(15):8921-8926.
44. Zangemeister-Wittke U. Antisense to apoptosis inhibitors facilitates chemotherapy and TRAIL-induced death signaling. Ann N Y Acad Sci. 2003; 1002: 90-94.
45. Nita ME, Nagawa H, Tominaga O, et al. 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer. 1998; 78(8):986-992.
46. Liu XH, Yao S, Kirschenbaum A, Levine AC. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Res. 1998; 58(19):4245-4249.
47. Hattori K, Matsushita R, Kimura K, Abe Y, Nakashima E. Synergistic effect of indomethacin with adriamycin and cisplatin on tumor growth. Biol Pharm Bull. 2001;24(10):1214-1217.
48. Ho EA, Piquette-Miller M. Regulation of multidrug resistance by pro-inflammatory cytokines. Curr Cancer Drug Targets. 2006;6(4):295-311.
49. Kang HK, Lee E, Pyo H, Lim SJ. Cyclooxygenase-independent down-regulation of multidrug resistance-associated protein-1 expression by celecoxib in human lung cancer cells. Mol Cancer Ther. 2005;4(9):1358-1363.
50. Zatelli MC, Luchin A, Piccin D, et al. Cyclooxygenase-2 inhibitors reverse chemoresistance phenotype in medullary thyroid carcinoma by a permeability glycoprotein-mediated mechanism. J Clin Endocrinol Metab. 2005; 90(10):5754-5760.
51. Kobayashi S, Okada S, Hasumi T, Sato N, Fujimura S. Modulating activity of indomethacin to vincristine cytotoxicity in various human carcinoma cells. Tohoku J Exp Med. 1998;186(4):313-322.
52. Fosslien E. Cardiovascular complication of non-steroidal anti-inflammatory drugs. Ann Clin Lab Sci. 2005;35(4):347-385.
53. Jin DZ, Yin LL, Ji XQ, Zhu XZ. Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. Eur J Pharmacol. 2006;549(1-3):166-172.
54. LaValle JB, ed. The Cox-2 connection: natural breakthrough treatment for arthritis, Alzheimer’s, and cancer. Healing Arts Press, Vermont, 2001: 69-86.
55. Haqqi TM, Anthony DD, Gupta S, et al. Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci U S A. 1999; 96(8):4524-4529.
56. Tong X, Yin L, Giardina C. Butyrate suppresses COX-2 activation in colon cancer cells through HDAC inhibition. Biochem Biophys Res Commun. 2004; 317(2):463-471.
57. Park W, Lim W, Cho J, Inoue H, Rhyu MR, Lee Y. Inhibitory effects of ginsenoside-Rb1 on activation of the 12-O-tetradecanoylphorbol 13-acetate-induced cyclooxygenase-2 promoter. Planta Med. 2006;72(3):272-275.
58. Muñoz-Espada AC, Watkins BA. Cyanidin attenuates PGE2 production and cyclooxygenase-2 expression in LNCaP human prostate cancer cells. J Nutr Biochem. 2006;17(9):589-596.
59. Yuk TH, Kang JH, Lee SR, et al. Inhibitory effect of Carthamus tinctorius L. seed extracts on bone resorption mediated by tyrosine kinase, COX-2 (cyclooxygenase) and PG (prostaglandin) E2. Am J Chin Med. 2002;30(1):95-108.
60. Hou DX, Fujii M, Terahara N, Yoshimoto M. Molecular mechanisms behind the comopreventive effects of anthocyanidins. J Biomed Biotechnol. 2004;2004(5):321-325.
61. Shishodia S, Amin HM, Lai R, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol. 2005;70(5):700-713.
62. Su CC, Chen GW, Lin JG, Wu LT, Chung JG. Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B /p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. Anticancer Res. 2006; 26(2A):1281-1288.
63. Lev-Ari S, Strier L, Kazanov D, et al. Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clin Cancer Res. 2005;11(18):6738-6744.
64. Bensky D, Gamble A, ed. Chinese herbal medicine materia medica. Eastland Press, Washington. 1993: 77-80.
65. Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwara H. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol. 1999;66(2):227-233.
66. Lee DU, Kang YJ, Park MK, et al. Effects of 13-alkyl-substituted berberine alkaloids on the expression of COX-II, TNF-alpha, iNOS, and IL-12 production in LPS-stimulated macrophages. Life Sci. 2003;73(11):1401-1412.
67. Lee DU, Kang YJ, Shirwaikar A, Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004;203(2):127-137.
68. Shirwaikar A, Rajendran K, Punitha IS. In vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid berberine. Biol Pharm Bull. 2006;29(9):1906-1910.
69. Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther. 2006;5(2):296-308.
70. Katiyar SK, Meeran SM, Katiyar N, Akhtar S. p53 cooperates berberine-induced growth inhibition and apoptosis of non-small cell human lung cancer cells in vitro and tumor xenograft growth in vivo. Mol Carcinog. 2009: 48(1):24-37.
71. Mitani N, Murakami K, Yamaura T, Ikeda T, Saiki I. Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. Cancer Lett. 2001;165(1):35-42.
72. Kang JX, Liu J, Wang J, He C, Li FP. The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by upregulation of interferon-beta and TNF-alpha in human breast cancer cells. Carcinogenesis. 2005;26(11):1934-1939.
73. Dommels YE, Haring MM, Keestra NG, et al. The role of cyclooxygenase in n-6 and n-3 polyunsaturated fatty acid mediated effects on cell proliferation, PGE(2) synthesis and cytotoxicity in human colorectal carcinoma cell lines. Carcinogenesis. 2003;24(3):385-392.
74. Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T. Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. Cancer Res. 2008; 68(2):553-560.
75. Kang JX. From fat to fat-1: a tale of omega-3 fatty acids. J Membr Biol. 2005;206(2):165-172.
76. Bommareddy A, Arasada BL, Mathees DP, Dwivedi C. Chemopreventive effects of dietary flaxseed on colon tumor development. Nutr Cancer. 2006;54(2):216-222.
77. Lin CS, Kuo CL, Wang JP, et al. Growth inhibitory and apoptosis inducing effect of Perilla frutescens extract on human hepatoma HepG2 cells. J Ethnopharmacol. 2007; 112(3):557-567.
78. Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 2008;10(3):511-545.
79. Lin HL, Liu TY, Wu CW, Chi CW. Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel. Br J Cancer. 1999;81(3):416-422.
80. Lin HL, Liu TY, Lui WY, Chi CW. Up-regulation of multidrug resistance transporter expression by berberine in human and murine hepatoma cells. Cancer.1999;85 (9):1937-1942.
81. Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 2002;62(13):3868-3875.
82. Rigas B, Sun Y. Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer. Br J Cancer. 2008;98(7):1157-1160.
83. Di Giacomo C, Acquaviva R, Lanteri R, Licata F, Licata A, Vanella A. Nonproteic antioxidant status in plasma of subjects with colon cancer. Exp Biol Med (Maywood). 2003;228(5):525-528.
84. Nagy B, Mucsi I, Molnar J, Varga A, Thurzo L. Chemosensitizing effect of vitamin C in combination with 5-fluorouracil in vitro. In Vivo. 2003;17(3):289-292.
85. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NF-kappaB transcription factors. J Neurochem. 2007;102(2):522-538.
86. Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer Treat Rev. 2007;33(5):407-418.
87. Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev. 2008; 11(1):1-15.
88. Wang HW, Lin CP, Chiu JH, et al. Reversal of inflammation-associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin. Int J Cancer. 2007; 120(9):2019-2027.
89. Liu J, He C, Zhou K, Wang J, Kang JX. Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells. Biochem Biophys Res Commun. 2009;378(2):174-178.
90. Ung CY, Li H, Cao ZW, Li YX, Chen YZ. Are herb-pairs of traditional Chinese medicine distinguishable from others? Pattern analysis and artificial intelligence classification study of traditionally defined herbal properties. J Ethnopharmacol. 2007;111(2):371-377.
91. McLeod HL. Clinically relevant drug-drug interactions in oncology. Br J Clin Pharmacol. 1998;45(6):539-544.
92. Gurley BJ, Gardner SF, Hubbard MA. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther. 2004;76(5): 428-440.

Figure 1. Overview of eicosanoid metabolism and its relationship with cancer. AA, arachidonic acid; COX2, cyclooxygenase; EET, epoxyeicosatrienoic acids; HETE, hydroxyeicosatetraenoic acids; LOXs, lipoxygenases; LT, leukotriene; PG, prostaglandin; TX, thromboxane.

Tags: cancer, Chemotherapy, Natural Anti-inflammatory Agents