RB- -inhibitors of Cox2,Aromatase,phospholipase A effect on inhibn of nonher2+ ER+ bc

[Lani]

her2 breast cancer is a different animal--but some of the same enzymes, genes may be involved:

Environ Health Perspect. 2007 Dec;115(12):1727-31. Links
Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation.

Markaverich BM, Crowley J, Rodriquez M, Shoulars K, Thompson T.
Department of Molecular and Cellular Biology, Baylor Colloege of Medicine, Houston, TX 77030, USA. barrym@bcm.tmc.edu
BACKGROUND: We characterized an endocrine disruptor from ground corncob bedding material that interferes with male and female sexual behavior and ovarian cyclicity in rats and stimulates estrogen receptor (ER)-positive and ER-negative breast cancer cell proliferation. The agents were identified as an isomeric mixture of tetrahydrofurandiols (THF-diols; 9,12-oxy-10,13-dihydroxy-octadecanoic acid and 10,13-oxy-9,12-dihydroxyoctadecanoic acid). Synthetic THF-diols inhibited rat male and female sexual behavior at oral concentrations of 0.5-1 ppm, and stimulated MCF-7 human breast cancer cell proliferation in vitro. OBJECTIVES: Because THF-diols are derived from lipoxygenase and cyclooxygenase pathways, we suspected that these compounds may regulate cell proliferation by modulating specific enzymatic sites involved in linoleic acid metabolism including phospholipase A(2) (PLA2), lipoxygenases (LOX-5 and LOX-12), cyclooxygenases (COX-1 and COX-2), and closely coupled enzymes including aromatase (AROM). METHODS: MCF-7 human breast cancer cells were treated with inhibitors for PLA2 (quinacrine), lipoxygenases (LOX-5 and LOX-12; baicalein, REV-5091, nordihydroguaiaretic acid), cyclooxygenases (COX-1, COX-2, indomethacin), and AROM (formestane). The effects of these enzyme inhibitors on cell proliferation in response to THF-diols or estradiol (E(2)) were assessed. THF-diol modulation of the expression (RNA and protein) of these enzymes was also evaluated by quantitative real-time PCR (QPCR) and Western blot analyses. RESULTS: The enzyme inhibition and gene expression (RNA and protein) studies identified PLA2, LOX-5, LOX-12, COX-2, and perhaps AROM as likely sites of THF-diol regulation in MCF-7 cells. COX-1 was not affected by THF-diol treatment. DISCUSSION: THF-diol stimulation of MCF-7 cell proliferation is mediated through effects on the expression of the PLA2, COX-2, LOX-5, and LOX-12 genes and/or their respective enzyme activities. The products of these enzymes, including prostaglandins, hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecenoic acids (HODEs), are well-established mitogens in normal and malignant cells. Therefore, it is likely that these compounds are involved in the mechanism of action of THF-diols in breast cancer cells. Although the formestane inhibition studies suggested that AROM activity might be modulated by THF-diols, this was not confirmed by the gene expression studies.
PMID: 18087590 [PubMed - in process]

[R.B.]

Many thank you for that post Lani. I had not come across THF-diols before.

I am struggling to understand even in the most general terms where they fit.

I looked up THF-diols and found this, which raises a host of questions.

http://www.encyclopedia.com/doc/1G1-168423874.html

RB

[R.B.]

They are researching at adding corn cob extract to oils.

http://www.sciencedirect.com/science...8a17f46644960d

[R.B.]

I am out of my depth here.

I post it as a way of saving it, to flag up the warning in the article as to the possible dangers of certain types of animal bedding, and in case of interest to HER2 experts.

I have been unable so far to determine if there is any danger of these products being present in corn oils, or if cobs are present in the extraction process.

But this is looking at LOXs which are products of Omega Six, linoleic acid. LOXs are a product of Omega Six.

Cutting down Omega six and balancing with Omega Three will reduce the availability of LOX products.

HER is part of the epidermal growth factor family, but I do not know if this article has any bearing specificaly on HER2.


Leukotoxin Diols from Ground Corncob Bedding Disrupt Estrous Cyclicity in Rats and Stimulate MCF-7 Breast Cancer Cell Proliferation

http://www.pubmedcentral.nih.gov/art...?artid=1314908

"In addition, although the THF-diols and LTX-diols on ground corncob extracts stimulate estrogen-dependent (MCF-7 cells) cell proliferation, the compounds also stimulate cell proliferation in estrogen-independent breast cancer (MDA-MD-231 cells) and prostate cancer (LNCap vs. PC-3 cells) cell lines (Markaverich et al. 2002a, 2002b) in vitro. "


"Epidermal growth factor (EGF) stimulation of cell proliferation involves membrane-associated PLA-mediated release of arachidonic acid and linoleic acids from the cell membrane. The conversion of these fatty acids to prostaglandins (Nolan et al. 1988) or linoleic acid metabolites [9-hydroxyoctadecadienoic acid (9-HODE), 12-HODE, and 13-HODE] mediates EGF stimulation of [3H]thymidine incorporation into DNA (Glasgow and Eling 1990, 1994), cell cycle transition, and apoptosis (Durgam and Fernandes 1997; Kachhap et al. 2000; Tong et al. 2002). Breast cancer specimens contain higher concentrations of PLA than do benign breast tissues, and low PLA activity is associated with longer disease-free interval and survival even though no relationship was noted between PLA and ER or progesterone receptor status (J. Yamashita et al. 1995; S. Yamashita et al. 1993, 1994). In MCF-7, MCF-10, and MDA-MB-231 human breast cancer cells, LOX, but not COX, inhibitors block EGF/transforming growth factor α stimulation of 12-HODE, and 13-HODE production and cellular proliferation (Natajaran et al. 1997; Reddy et al. 1997). A number of LOX inhibitors including nordihydroguaiaretic acid, baicalein, and Rev-5901 inhibit MCF-7 and MDA-MB-231 cell proliferation and induce apoptosis. LOX products [5-eicosatrienoic acid (5-HETE), 12-HETE] reverse these effects (Natajaran et al. 1997). EGF stimulation of MCF-7 cell proliferation causes a dose-dependent increase in the formation of LOX products, including 12-HETE (Tong et al. 2002). Thus, LOX products (HODEs, HETEs) stimulate proliferation of these cells. THF-diols and LTX-diols are derived from linoleic acid pathways that generate HODEs and HETEs. It is possible that the THF-diols and LTX-diols modulate cellular proliferation by controlling the synthesis of these linoleic acid metabolites and/or by mimicking these compounds as mitogenic agents."

"Uncharacterized chemical agents in these materials may include the LTX-diols and THF-diols. In addition to being used as bedding for small animals, ground or milled corncob is also used as adsorbent for chemical spills, a polishing agent for metals, and a pesticide carrier for insects such as spider mites and fire ants. This product is also used as cat litter. Thus, exposure of the general public to toxic agents in ground corncob is likely. Clearly, these fatty acid diols stimulate breast cancer cell proliferation in vitro and disrupt reproductive function in rats at relatively low concentrations. Sustained exposure to such compounds may represent a significant health hazard."

[R.B.]

More questions and caveats than answers.




http://www.ehponline.org/members/200...rich-full.html

A Novel Endocrine-Disrupting Agent in Corn with Mitogenic Activity in Human Breast and Prostatic Cancer Cells

Barry Markaverich,1,2 Shaila Mani,2 Mary Ann Alejandro,1,2 Andrea Mitchell,2 David Markaverich,1,2 Trellis Brown,1,2 Claudia Velez-Trippe,1,2 Chris Murchison,1 Bert O'Malley,2 and Robert Faith1

1Center for Comparative Medicine and 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA


"Extracts from fresh corn kernels or cob also contained this mitogenic activity when assayed in MCF-7 cells (Figure 10A) and the mitogen fractionated on Spice C18 cartridges in a manner indistinguishable (Figure 10B) from that isolated from ground corncob bedding (Figure 5B). A similar mitogenic activity in a corn tortilla extract preparation (80% methanol eluate from C18 mini-columns) was detected after addition to cultured MCF-7 cells (Figure 11), demonstrating that human food products derived from corn contain this mitogenic material. We suspect that corn oil also contains this substance(s) but this has not been investigated."

"In summary, although the potential effects of CM on human populations remains to be resolved, the studies described in this article show that in addition to ground corncob bedding, fresh corn on the cob (kernels and cob) and corn tortillas contain CM. The CM activity from these foods stimulates breast and prostatic cancer cellular proliferation and will likely disrupt endocrine function and behavior as well."

"Thus, CM present in corn products may complicate experimental results in animal studies, and human exposure to this endocrine-disrupting agent is likely. Although it is well established that consumption of high-fat diets (23-24% corn oil) increases the incidence, growth, and metastases of mammary, liver, and colon cancer in a variety of experimental systems (47-49), the question of whether acute or sustained exposure to CM and/or related compounds, alone or in combination, represents a significant health problem remains to be resolved."

http://www.ehponline.org/members/200...rich/fig10.jpg