thinking of Lyn--new lead from" OZ "for treating bone mets from breast cancer

[Lani]

1: Cancer Res. 2006 May 15;66(10):5363-70. Links

Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model.

Thai le M, Labrinidis A, Hay S, Liapis V, Bouralexis S, Welldon K, Coventry BJ, Findlay DM, Evdokiou A.

Department of Orthopaedics, Royal Adelaide Hospital, Adelaide University.

Breast cancer is the most common carcinoma that metastasizes to bone. To examine the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against breast cancer growth in bone, we established a mouse model in which MDA-MB-231 human breast cancer cells were transplanted directly into the marrow cavity of the tibiae of athymic nude mice producing osteolytic lesions in the area of injection. All vehicle-treated control animals developed large lesions that established in the marrow cavity, eroded the cortical bone, and invaded the surrounding soft tissue, as assessed by radiography, micro-computed tomography, and histology. In contrast, animals treated with recombinant soluble Apo2L/TRAIL showed significant conservation of the tibiae, with 85% reduction in osteolysis, 90% reduction in tumor burden, and no detectable soft tissue invasion. Tumor cells explanted from Apo2L/TRAIL-treated animals were significantly more resistant to the effects of Apo2L/TRAIL when compared with the cells explanted from the vehicle-treated control animals, suggesting that prolonged treatment with Apo2/TRAIL in vivo selects for a resistant phenotype. However, such resistance was readily reversed when Apo2L/TRAIL was used in combination with clinically relevant chemotherapeutic drugs, including taxol, etoposide, doxorubicin, cisplatin, or the histone deacetylase inhibitor suberoylanilide hydroxamic acid. These studies show for the first time that Apo2L/TRAIL can prevent breast cancer-induced bone destruction and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. (Cancer Res 2006; 66(10): 5363-70).

PMID: 16707463 [PubMed - in process]

Is anyone in Australia ready to do/doing a clinical trial?

[R.B.]

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/query.fcgi?db=PubMed&cmd=search&term=APO2+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
Click here to read
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]

[R.B.]

This trial links COX 2 inhibition with increase in TRAIL related apoptosis

RB


http://cancerres.aacrjournals.org/cgi/content/abstract/65/24/11447

ABSTRACT


Cell and Tumor Biology
Cyclooxygenase-2 Inhibition Sensitizes Human Colon Carcinoma Cells to TRAIL-Induced Apoptosis through Clustering of DR5 and Concentrating Death-Inducing Signaling Complex Components into Ceramide-Enriched Caveolae
Sophie Martin1,3, Darren C. Phillips1, Kinga Szekely-Szucs1, Lynda Elghazi2, Fabienne Desmots2 and Janet A. Houghton1

1 Division of Molecular Therapeutics, Department of Hematology-Oncology; 2 Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee and 3 UMR 7175-LC1, Pharmacologie et Physicochimie, Faculté de Pharmacie, Université Louis Pasteur, Illkirch, France

Requests for reprints: Janet A. Houghton, Division of Molecular Therapeutics, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: 901-495-3465; Fax: 901-495-3966; E-mail: janet.houghton@stjude.org.

Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane. (Cancer Res 2005; 65(24): 11447-58)