COX2 and BC a cumulative knowledge thread

[R.B.]

In my web wanders through the world of fats I keep finding articles linking COX2 expression to BC. The exclusive raw materials for the COX2 production line are members of the omega six and three families AA and EPA respectively.

To save clogging up the Greek Diet thread with technical information I will post the COX2 related items I find to this thread to keep them in one place.

At the most basic level all you need to understand is that Omega six and three compete for the COX2 production line. The COX2 production line has a limited capacity.

Like any production line you can limit what comes out the other end by limiting the amount that is put in.

Limit omega six intake and balance it with omega three and you will limit the production of Omega Six Cox 2 products.

Omega six COX2 products directly connect to aromatase which connects to oestrogen production. COX 2 also connects into immune systems etc.

Here is the first

RB

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum
Inhibition of cyclooxygenase-2 and induction of apoptosis in estrogen-nonresponsive breast cancer cells by Antrodia camphorata.
Hseu YC, Chen SC, Tsai PC, Chen CS, Lu FJ, Chang NW, Yang HL.

"Analysis of the study data suggests that A. camphorata exerts growth inhibition on (highly invasive) [(MDA-MB-231)] estrogen-nonresponsive human breast cancer cells through apoptosis induction associated with COX-2 inhibition,"


Department of Cosmeceutics, China Medical University, Taichung, Taiwan.

[R.B.]

Two mechanisms are recognised here - gene expression and enzyme activity.

RB

Cyclooxygenase-2 directly regulates gene expression of P450 Cyp19 aromatase promoter regions pII, pI.3 and pI.7 and estradiol production in human breast tumor cells.
Prosperi JR, Robertson FM.

Department of Molecular Virology, Immunology, and Medical Genetics, The Integrated Biomedical Science Graduate Program, The Ohio State University College of Medicine, 2184 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.

"These studies demonstrate that Cox-2 directly regulates gene expression of specific aromatase promoter regions and regulates aromatase enzyme activity. Agents that inhibit Cox-2 or block the biological effects of PGE2 may be useful in significantly limiting aromatase activity and proliferation of human breast tumor cells regardless of the presence of Cox-2."

[R.B.]

Reduced BRAC1 increases aromatase products.

It looks as if BRAC 1 may act as an aromatase inhibitor (and when BRAC1 mutates does it stop doing that ? - this seems to be the question being asked between the lines)

BRCA1 negatively regulates the cancer-associated aromatase promoters I.3 and II in breast adipose fibroblasts and malignant epithelial cells.
Lu M, Chen D, Lin Z, Reierstad S, Trauernicht AM, Boyer TG, Bulun SE.

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.

"CONCLUSIONS: Selective inhibition of aromatase expression by BRCA1 binding to the I.3/II tumorigenic promoter region may be an important protective mechanism against breast cancer development."

[R.B.]

Thought provoking indeed.

RB



HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism.
Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ.

Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

"Previously, we found that overexpression of HER-2/neu was associated with increased levels of COX-2 in human breast cancers. Here, we show that overexpression of HER-2/neu is also associated with increased aromatase activity. These results suggested the possibility that COX-2 was the functional intermediate linking HER-2/neu and aromatase......Collectively, our data indicate that COX-2 is the functional intermediate linking HER-2/neu and aromatase and suggest that inhibitors of PGE(2) synthesis will suppress estrogen biosynthesis in breast tissue."

[R.B.]

I read this a while ago. It is a fascinating and informative article.

RB



Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches.
Brueggemeier RW, DÃ*az-Cruz ES.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Brueggemeier.1@osu.edu




"High levels of COX-2 expression result in higher levels of prostaglandin E2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE2 produced by COX enzymes may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development."

[R.B.]

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum
Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells.
Tari AM, Simeone AM, Li YJ, Gutierrez-Puente Y, Lai S, Symmans WF.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. atari@mdanderson.org


"We speculate that high levels of COX-2 induce drug resistance in ERalpha-positive breast tumors, thus reducing the survival rate of patients with such tumors."

"Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERalpha-positive breast cancer cells."

[R.B.]

Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer.
Brueggemeier RW, DÃ*az-Cruz ES, Li PK, Sugimoto Y, Lin YC, Shapiro CL.

College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA. brueggemeier.1@osu.edu

"In summary, pharmacological regulation of aromatase and cyclooxygenases can act locally in an autocrine fashion to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer."

[R.B.]

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells.
DÃ*az-Cruz ES, Shapiro CL, Brueggemeier RW.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.

"Thus, COX inhibitors decrease aromatase mRNA expression and enzymatic activity in human breast cancer cells in culture, suggesting that these agents may be useful in suppressing local estrogen biosynthesis in the treatment of hormone-dependent breast cancer."

[R.B.]

http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

Novel sensitizing agents: potential contribution of COX-2 inhibitor for endocrine therapy of breast cancer.
Saji S, Hirose M, Toi M.

Department of Surgery and Breast Oncology, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. ss-saji@wa2.so-net.ne.jp

Enhancement of the therapeutic effect of conventional drugs is currently an active treatment strategy for breast cancer, as shown in the clinical application of trastuzumab with chemotherapeutic agents, which prolonged survival even for metastatic disease. Cyclo-oxygenase 2(COX-2)inhibitors, which are chemoprevention agents for familial polyposis coli, are now contributing to this strategy in combination with chemotherapeutic and endocrine drugs. As an endocrine application, overexpression of COX-2 contributes to increased expression of aromatase in the breast tumor. In addition, it is also known to promote rich micro-vessels within the tumor through up-regulation of prostaglandin E2(PGE2), which can induce vascular endothelial growth factor(VEGF)and basic fibroblast growth factor(bFGF)in cancer cells, and can directly modulate endothelial cell proliferation. Since both rich vasculature and accelerated estrogen synthesis are thought to contribute to unfavorable conditions for the response to endocrine therapy, inhibiting COX-2 with COX-2 inhibitors is a promising strategy to potentiate endocrine therapy.

[R.B.]

J Gynecol Obstet Biol Reprod (Paris). 1981;10(3):197-201. Related Articles, Links

[Prostaglandins and benign mastopathies (author's transl)]

[Article in French]

Rolland PH, Martin PM, Bourry M, Serment H.

"During both phases of their menstrual cycle, women who suffer from benign mastopathies evidence hormonal deficiency, which is total although of variable magnitude, as shown by oestradiol (E2) and progesterone (p) plasma levels. by contrast, these women show a concomitant and large rise of prostaglandin E2 (PGE2) plasma level."

[R.B.]

British Journal of Cancer (2006) 94, 346-350.
doi:10.1038/sj.bjc.6602942 Published online 17 January 2006

COX inhibitors and breast cancer

D Mazhar1, R Ang1 and J Waxman1

1Department of Cancer Medicine, Division of Medicine, Faculty of Medicine, Imperial College London, Room 1014 Garry Weston Centre, Hammersmith Campus, Du Cane Road, London W12 0NN, UK

http://www.nature.com/bjc/journal/v9.../6602942a.html

" Minireview

British Journal of Cancer (2006) 94, 346-350.
doi:10.1038/sj.bjc.6602942 Published online 17 January 2006

COX inhibitors and breast cancer

D Mazhar1, R Ang1 and J Waxman1

1Department of Cancer Medicine, Division of Medicine, Faculty of Medicine, Imperial College London, Room 1014 Garry Weston Centre, Hammersmith Campus, Du Cane Road, London W12 0NN, UK



Correspondence to: Professor J Waxman, E-mail: j.waxman@imperial.ac.uk

Received 3 October 2005; revised 6 December 2005; accepted 6 December 2005; published online 17 January 2006



"There is considerable evidence to suggest that prostaglandins play an important role in the development and growth of cancer. The enzyme cyclo-oxygenase (COX) catalyses the conversion of arachidonic acid to prostaglandins. In recent years, there has been interest in a possible role for COX inhibitors in the prevention and treatment of malignancy."

[R.B.]

Gurpreet Singh-Ranger1, Mohamed Salhab1 and Kefah Mokbel1, 2 Contact Information
(1) St George’s University of London, London, UK
(2) The London Breast Institute, The Princess Grace Hospital, 42-52 Nottingham Place, London, W1M 3FD, UK

Received: 28 May 2007 Accepted: 1 June 2007 Published online: 12 July 2007

http://www.springerlink.com/content/8310235677lm7875/

"Abstract There is a growing body of evidence that COX-2 expression s a fundamental step in breast cancer pathogenesis acting through prostaglandin-dependent and independent mechanisms. Epidemiological studies suggest that NSAIDs confer a moderate degree of benefit against breast cancer. However further work is required to establish how this enzyme system can be best manipulated for therapeutic benefit."

[R.B.]

REVIEW
Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer

* D. PEREG11Department of Internal Medicine A, Sapir Medical Center, Kfar Sava &
* M. LISHNER1,21Department of Internal Medicine A, Sapir Medical Center, Kfar Sava2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; Israel

*
From the 1Department of Internal Medicine A, Sapir Medical Center, Kfar Sava; and 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; Israel

"Whilst their anti-inflammatory effect is well known, recent studies have demonstrated an unexpected effect in both the prevention and treatment of several types of cancer. The anticancerous effect of NSAIDs is believed to be mainly due to the inhibition of COX-2, which is overexpressed in many types of cancer and may play a major role in tumourigenesis."

[R.B.]

Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture.
Rose DP, Connolly JM.

Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, New York 10595.

http://www.ncbi.nlm.nih.gov/sites/en...t_uids=2224849

"Linoleic acid, an omega 6 FA, stimulated MDA-MB-231 cell growth with an optimal effect at a concentration of 0.75 microgram/ml, whereas oleic acid, an omega 9 FA, produced growth stimulation at 0.25 microgram/ml but was inhibitory at higher concentrations. Docosahexaenoic acid exhibited a dose-related inhibition of cell growth at concentrations ranging from 0.5 to 2.5 micrograms/ml; eicosapentaenoic acid, also an omega 3 FA, was less effective. Similar inhibitory effects occurred with saturated FAs. Indomethacin, which at high concentrations is an inhibitor of both the cyclooxygenase- and lipoxygenase-catalyzed pathways of eicosanoid synthesis, suppressed cell growth stimulation by an otherwise optimal dose of linoleic acid when present at 40 micrograms/ml. Experiments with piroxicam, nordihydroguaiaretic acid, and esculetin, other inhibitors of eicosanoid biosynthesis with varying selectivity for enzymes of the prostaglandin and leukotriene pathways, indicated that MDA-MB-231 cell growth was dependent on leukotriene rather than prostaglandin production."

[mimiflower07]

i see...what does that mean in english. i was tired just reading that.lol
suzanne

[StephN]

Thanks for this thread, R.B.

I only just discovered it.

When I was pronounced NED after my extensive liver mets, my med onc told me that he wanted me to take Celebrex as he was interested in inhibiting COX2. I took that for almost three years, until the reports came out on the side effects.

The reason he recommended a COX2 inhibitor was that at that time all this research was just beginning but there was anecdotal evidence that a COX2 inhibitor was effective against prostate cancers. So, I have sort of put that out of my mind in the meantime, but glad to see the importance has been made clear now.

I wonder if I should be back on some form of COX2 inhibitor??

[Lani]

NSAIDs are both antiaromatase and antiangiogenic

Dr. David Feldman at Stanford had a clinical trial where he gave very large doses of vitamin D (large enough to cause kidney stones, but given in a course fashion time-wise that did not) plus Naprosyn (same ingredient as in Aleve). He got the idea as preclinically this decreased the growth of prostate cancer cells by more than 95%. WHEN given in men with METASTATIC (but mild) prostate cancer, the men's PSA stayed down as long as they stayed on the treatment. As no drug company funded the trial (nothing to make money on) they had to stop it and the men's PSAs went up when they stopped.

Last I heard, researchers at Stanford were trying too start a similar trial in breast cancer ie, vitamin D and NSAIDs.

I have heard a breast surgeon from MD Anderson, Anthony Lucci, expound on the NSAIDs vs breast cancer an area of interest in his research. Because of the problems w cox2 specific inhibitors he suggested NSAIDs.


This is not to suggest anyone take these drugs--I am not qualified to make that suggestion. Sounds like you asked your treating physician--something which never hurts.

[R.B.]

Omega six derivative is the source of most of the products Cox blockers / NSAIDS seek to block.

DHA is a COX blocker by blocking the creating of Omega Six chemicals.

SO balancing your Omega threes (And ensuring adequate long chain DHA /EPA) and sixes is a Cox blocking strategy.

Which is to to say that drugs don not have a valuable role, but for me balancing the Omega 3 and 6s has to be a good preventative strategy starting point.

You will find more information here.

http://her2support.org/vbulletin/sho...ght=greek+diet

Please discuss dietary changes with you medical advisor


RB.

[Barbara2]

I took Celebrex for 13 months after completing chemo. My onc said that there was some thought that it might work against the Cox 2 so it was worth a try, plus it might fight off aches from the Arimidex. I took 200mg twice daily. StephN, how much did you take each day?

Over time I became sick from the drug. Very lethargic, fatigued, foggy brain. When I stopped the Celebrex I felt better right away. (Although looking back, I wonder if some of those symptoms were from the Ativan which I eventually had to stop taking also.)

I still use Celebrex on occasion, but very seldom. Dr. Pegram advised to stay away from it.

[Rich66]

Biomed Pharmacother. 2009 Nov 14. [Epub ahead of print]
Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling.

Shirode AB, Sylvester PW.
College of Pharmacy, University of Louisiana, 700, University Avenue, Monroe, LA 71209-0470, United States.
The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, and the vitamin E isoform, gamma-tocotrienol, both display potent anticancer activity. However, high dose clinical use of selective COX-2 inhibitors has been limited by gastrointestinal and cardiovascular toxicity, whereas limited absorption and transport of gamma-tocotrienol by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Studies were conducted to characterize the synergistic anticancer antiproliferative effects of combined low dose celecoxib and gamma-tocotrienol treatment on mammary tumor cells in culture. The highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined control or treatment media. Treatment effects on COX-1, COX-2, Akt, NFkappaB and prostaglandin E(2) (PGE(2)) synthesis were assessed following a 3- or 4-day culture period. Treatment with 3-4muM gamma-tocotrienol or 7.5-10muM celecoxib alone significantly inhibited +SA cell growth in a dose-responsive manner. However, combined treatment with subeffective doses of gamma-tocotrienol (0.25muM) and celecoxib (2.5muM) resulted in a synergistic antiproliferative effect, as determined by isobologram analysis, and this growth inhibitory effect was associated with a reduction in PGE(2) synthesis, and decrease in COX-2, phospho-Akt (active), and phospho-NFkappaB (active) levels. These results demonstrate that the synergistic anticancer effects of combined celecoxib and gamma-tocotrienol therapy are mediated by COX-2 dependent and independent mechanisms. These findings also suggest that combination therapy with these agents may provide enhanced therapeutic response in breast cancer patients, while avoiding the toxicity associated with high-dose COX-2 inhibitor monotherapy.

PMID: 19954924 [PubMed - as supplied by publisher]