I have seen mentions of links with APO 2 and the fat pathways, and just looked up up again to check.
PPAR gamma is up expressed in BC but not normal cells.
DHA docasaHexaenoic acid is from memory a PPAR gamma activator, (see below).
VIZ ******* TAKING DHA WILL ACTIVATE PPAR GAMMA WHICH WILL REDUCE FLIP?? if I am reading this correctly. ********
All of which might be another good reason for balancing the omega threes and sixes and taking a fish oil or equivalent supplement for DHA.
Is this an example of where the obvious conclusion has no "merit" to a drugs corporation, so the obvious is rearranged by researchers into a search for a derivative which can be marketed as a drug ( which conclusion would be more likely to earn a plaudit ? ) ( Human nature and dynamic at work?]
My big cry - why do govts not fund trials looking at fats intake and BC using fat biopsies from breast, abdominal and gluteal as reference points. It has been done before using breat biopsies and shown 70% differenatials in invasivity dependent of fat type in diet as reflected in breast tissue. (Which if acccurate is a bigger differential than any drug I am aware of can claim)
RB
ABSTRACT
http://www.ncbi.nlm.nih.gov/entrez/q...PO2+Trail+ppar
1: J Biol Chem. 2002 Jun 21;277(25):22320-9. Epub 2002 Apr 8. Related Articles, Links
Click here to read
An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis.
Kim Y, Suh N, Sporn M, Reed JC.
Burnham Institute, La Jolla, California 92037, USA.
TRAIL (Apo2 ligand) is a member of the tumor necrosis factor (TNF) family of cytokines that induces apoptosis. Because TRAIL preferentially kills tumor cells, sparing normal tissues, interest has emerged in applying this biological factor for cancer therapy in humans. However, not all tumors respond to TRAIL, raising questions about resistance mechanisms. We demonstrate here that a variety of natural and synthetic ligands of peroxisome proliferator-activated receptor-gamma (PPAR gamma) sensitize tumor but not normal cells to apoptosis induction by TRAIL. PPAR gamma ligands selectively reduce levels of FLIP, an apoptosis-suppressing protein that blocks early events in TRAIL/TNF family death receptor signaling. Both PPAR gamma agonists and antagonists displayed these effects, regardless of the levels of PPAR gamma expression and even in the presence of a PPAR gamma dominant-negative mutant, indicating a PPAR gamma-independent mechanism. Reductions in FLIP and sensitization to TRAIL-induced apoptosis were also not correlated with NF-kappa B, further suggesting a novel mechanism. PPAR gamma modulators induced ubiquitination and proteasome-dependent degradation of FLIP, without concomitant reductions in FLIP mRNA. The findings suggest the existence of a pharmacologically regulated novel target of this class of drugs that controls FLIP protein turnover, and raise the possibility of combining PPAR gamma modulators with TRAIL for more efficacious elimination of tumor cells through apoptosis.
PMID: 11940602 [PubMed - indexed for MEDLINE]
DHA metabolites are PPAR gamma activators?
1: Bioorg Med Chem Lett. 2005 Feb 1;15(3):517-22. Related Articles, Links
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Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents.
Yamamoto K, Itoh T, Abe D, Shimizu M, Kanda T, Koyama T, Nishikawa M, Tamai T, Ooizumi H, Yamada S.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
yamamoto.mr@tmd.ac.jp
We found that putative metabolites of docosahexaenoic acid (DHA) are strong PPARgamma activators and potential antidiabetic agents. We designed DHA derivatives based on the crystal structure of PPARgamma, synthesized them and evaluated their activities in vitro and in vivo. The efficacy of 5E-4-hydroxy-DHA 2a as a PPARgamma activator was about fourfold stronger than that of pioglitazone. Furthermore, the 4-keto derivative (10b) showed antidiabetic activity in animal models without producing undesirable effects such as obesity and hepatotoxicity.
PMID: 15664804 [PubMed - indexed for MEDLINE]