COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin

COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin

Some previous studies have found worse prognosis among cyclooxygenase-2 (COX-2)-expressing breast cancers. Aspirin and NSAIDs inhibit COX-2. Three studies, including ours, have reported a survival advantage among women with breast cancer who take either aspirin or NSAIDs. Through this study we hypothesized that in the Nurses’ Health Study (NHS), COX-2 expression would be associated with worse prognosis, and aspirin use would be associated with better survival particularly among women with COX-2 positive tumors. In this study we investigated 2,001 women presenting with invasive breast cancers stained for COX-2 by immunohistochemistry. Tumor prognostic factors were from medical records. Aspirin use was assessed at least 12 months after diagnosis and updated. Cause of death was identified from death certificates. Statistical analyses included logistic regression of prognostic factors with COX-2 status as the outcome, and proportional hazards regression with breast cancer death as the outcome. Tumor COX-2 expression was associated with higher diagnostic stage. Compared with stage I, the RR(95% CI) for stages II-IV were 1.16 (0.93-1.45), 1.68 (1.27-2.22), and 1.76 (0.93-3.32). COX-2 expression was associated with lobular compared with ductal histology (1.40 [1.02-1.92]), and estrogen receptor positive compared with negative (2.22 [1.66-2.95]). The RR(95% CI) of breast cancer death for current aspirin use was similar for women with COX-2-positive and COX-2-negative tumors; 0.64 (0.43-0.96) and 0.57 (0.44-0.74), respectively. In the NHS, COX-2 breast cancer expression was associated with higher stage at diagnosis. The survival benefit associated with aspirin use did not differ by COX-2 status. COX-2 breast cancer expression is associated with worse prognosis. If aspirin truly impacts breast cancer survival, then it is not solely via COX-2.
Holmes MD, Chen WY, Schnitt SJ, Collins L, Colditz GA, Hankinson SE, Tamimi RM. Breast Cancer Res Treat. 2011 Jul 5.

COX-2 as Possible Target for the Inhibition of PGE2 Production by Rikko-san in Activated Macrophage
Rikko-san (Li Xiao San) is one of the Kampo medicines (Japanese traditional medicines) and is composed of five major ingredients, Kanzo (gan zao), Shoma (sheng ma), Ryutan (long dan), Saishin (xi xin) and Bofu (fang fang). RKS has been reported to be effective in controlling oral pain caused by dental caries, pulpitis, periodontitis and tooth extraction, but its precise mechanism of anti-inflammatory effect is still unclear. In the arachidonic acid (AA) cascade, two enzymes are involved in the production of prostaglandin (PG) E2. PG synthesis begins with the liberation of AA, the prime precursor, from membrane phospholipids by phospholipase A2 (PLA2).
We have previously reported that Rikko-san (RKS) inhibited the lipopolysaccharide (LPS)-stimulated prostaglandin (PG) E2 in mouse macrophage-like RAW264.7 cells without affecting the expression of cyclooxygenase (COX)-2. Here RKS inhibition of the enzyme activity of both COX-1 and COX-2 proteins was investigated. Western blot analysis showed that RKS did not significantly change the S-nitrosylated COX-2 protein level. On the other hand, RKS inhibited the PG production catalyzed by purified COX-2, more effectively than that catalyzed by purified COX-1. These results suggest that RKS inhibits the PGE2 production by selectively inhibiting the COX-2 activity in activated macrophages.
Horio N, Hashimoto K, Kato T, et al. In Vivo. May-June 2008 vol. 22 no. 3 333-336

COX-2 Reducing Herbs/Compounds
I. Herbs
Chuan Xiong-Ligusticum Chuanxiong
Cui Yun Cao-Selaginella uncinata
Deng Long Guo-Physalis peruviana
Ding Xiang Luo Le-Ocimum gratissimum
E Zhu-Zedoariae rhizoma
Guang Ye Lu Hui-Aloe saponaria
Huang Qi-Astragalus membranaceus
Huang Qin-Scutellaria baicalensis
Huang Lian-Coptis
Jia Ma Chi Xian-Bacopa monniera
Jing Jie-Schizonepeta tenuifolia
Quan Xie-Scorpion
Shan Zha-Crataegus pinnatifida
Yin Xing Ye-Ginkgo biloba
Zhang Zhi-Antrodia camphorata

II. Compounds
2-methoxycinnamaldehyde
3-caffeoyl-4-dicaffeoylquinic acid
Apocynin
Baicalein
Curcumin
Cryptotanshinone
Ginsenoside
Hydroxycamptothecine
Luteolin
Madecassoside
Neoandrographolide
Paeoniflorin
Paeonol
Propyl gallate
Rosmanol
Salvianolic acid B
Wogonin

III. Example of Research
Cui Yun Cao-Selaginella uncinata
Inhibiting Action of Total Flavones from Selaginella uncinata on COX-2 mRNA Expression in HT-29 Cells
Objective: To investigate the action of total flavones from Selaginella uncinata ( Desv. ) Spring on cyclooxygenase-2 (COX-2) mRNA expression in carcinoma of colon cell line HT-29 ,and explore related molecular mechanism thereby. Method: Total flavones from Selaginella uncinata was used on TH-29 cells and there were four groups including high-dose group, midst-dose group, low-dose group and negative control group. The morphological change of the cells was observed by inverted microscope. The expressions of COX-2 mRNA were measured using reverse transcription polymerase chain reaction (RT-PCR) method. Caraphoresis gel photo auto- analysis system was used to detect the products. Result: Comparing with the negative control group, the total flavonoids groups could significantly inhibit the expressions of the COX-2 mRNA level in a dose-dependent manner. Conclusion: It can be concluded that the mechanisms may be that the total flavonoids can inhibit COX-2 in mRNA level. Then it can inhibit COX-2 protein expression. It may be one of the anti-tumor mechanisms of Selaginella uncinata.
Sun Yingzhen Chen Keli , Liu Zhen. Zhong Guo Yao Shi. 2010; (2): 163-164.

Huang Lian-Coptis
Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells.
Estrogen receptor (ER) antagonists have been widely used for breast cancer treatment, but the efficacy and drug resistance remain to be clinical concerns. The purpose of this study was to determine whether the extracts of coptis, an anti-inflammatory herb, improve the anticancer efficacy of ER antagonists. The results showed that the combined treatment of ER antagonists and the crude extract of coptis or its purified compound berberine conferred synergistic growth inhibitory effect on MCF-7 cells (ER+), but not on MDA-MB-231 cells (ER-). Similar results were observed in the combined treatment of fulvestrant, a specific aromatase antagonist. Analysis of the expression of breast cancer related genes indicated that EGFR, HER2, bcl-2, and COX-2 were significantly downregulated, while IFN-beta and p21 were remarkably upregulated by berberine. Our results suggest that coptis extracts could be promising adjuvant to ER antagonists in ER positive breast cancer treatment through regulating expression of multiple genes.
Liu J, He C, Zhou K, Wang J, Kang JX. Biochem Biophys Res Commun. 2009 Jan 9;378(2):174-8. Epub 2008 Nov 8.

Curcumin
Curcumin has bright prospects for the treatment of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life. While the aetiology of IBD is not understood well, it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines. Curcumin is a bioactive substance present in the rhizomes of the herb “Curcuma longa” which has been used for centuries in Asia, both in traditional medicine and in cooking as turmeric which gives food an exotic natural yellow color. Further, in recent years, a large number of research papers have reported intriguing pharmacologic effects associated with curcumin. These include inhibitory effects on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-alpha, interferon gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-kappaB), in addition to a strong anti-oxidant effect. NF-kappaB is a key factor in the upregulation of inflammatory cytokines that have a high profile in inflammatory diseases, suggesting that curcumin could be a novel therapeutic agent for patients with IBD. Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles, from the pro-inflammatory Th1 to the anti-inflammatory Th2 type. In human IBD, up to now, only one open study has achieved encouraging results. In this study, patients were given curcumin (360 mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD. The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-alpha, IFN-gamma, NF-kappaB and its unrivalled safety profile suggest that it has bright prospects in the treatment of IBD.
Hanai H, Sugimoto K. Curr Pharm Des. 2009;15(18):2087-94.