Sichuan Pepper extracts block the PAK1/Cyclin D1 pathwayand growth of NF1deficient ca

[Lani]

1: Cancer Biol Ther. 2006 Mar 12;5(3) [Epub ahead of print] Links

Sichuan Pepper Extracts Block the PAK1/Cyclin D1 Pathway and the Growth of NF1-Deficient Cancer Xenograft in Mice.

Hirokawa Y, Nheu T, Grimm K, Mautner V, Maeda S, Yoshida M, Komiyama K, Maruta1 H.

Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.

There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.

PMID: 16418572 [PubMed - as supplied by publisher]

[RhondaH]

should we buy this in bulk:)

Rhonda

Interesting website on this...One MORE thing to put on my salad (along w/ the turmeric and oregano)

http://www.all-foods-natural.com/dossier/anisepepper.html

[RobinP]

Yeh, sure if you promise to take your vitamin D and exercise to assist in decreasing the PI3K pathway.

[Becky]

Robin


I do exercise (and take Vitamin D) but how does the exercise help?

Thanks in advance

Becky

[RobinP]

Exercise will decrease blood sugar and insulin levels. Insulin levels and IGFBP-insulin growth factor binding protein have an inverse relationship. So as insulin levels go down when we exercise, IGFBP increases to bind up and decrease IGF-1R, insulin growth factor receptor-1 receptor. Now our goal is to obtain low IGF-1R as it has been," associated with risk of developing several cancers including breast carcinoma….. "see article below. To sum up the article below if we can lower IGF there is less of it around to ligand bind with; thus, we inhibit the PI3K pathway and resulting prolifertion of cancer cells.






Interactions of vitamin D analogues with downstream effectors of insulin-like growth factor 1 (IGF-I) signalling

LC Lowe, C Mørk Hansen & KW Colston

Oncology, Gastroenterology Endocrinology and Metabolism, St Georges Hospital Medical School, London, UK.

Raised levels of IGF-I have been associated with risk of developing several cancers including breast carcinoma. In addition to promoting mitogenesis in breast cancer cells, a number of observations suggest a role for inhibition of apoptosis by IGF-I receptor activation. Ligand binding to IGF-IR leads to activation of both the phosphoinositide-3'-kinase (PI3K) and the Ras/Raf/MAPKinase pathways. Deprivation of serum growth factors induces apoptosis in MCF-7 breast cancer cells and this effect can be abrogated by supplementation of serum free medium (SFM) with IGF-I via activation of the PI3K pathway. Co-treatment of MCF-7 cells with the vitamin D analogue EB1089 can attenuate the anti-apoptotic actions of IGF-I. To investigate the mechanism(s) by which EB1089 prevents IGF-I-mediated cell survival we compared interactions between this analogue and IGF-I in parental MCF-7 cells and a stable subclone (MCF-7/VDR) that is resistant to the growth inhibitory and apoptosis inducing effects of vitamin D. IGF-I promoted survival of parental and MCF-7/VDR cells in SFM such that >90% viability was obtained with cultures incubated with 4nM IGF-I for 4 days. Co-treatment with 100nM EB1089 attenuated the effects of IGF-I in parental but not MCF-7/VDR cells. Attenuation of IGF-I effects in parental cells was accompanied by a decrease in IGF-I-mediated PI3K activation (as assessed by levels of phosphorylated Akt). Using phosphospecific antibodies we obtained evidence that EB1089 treatment of parental cells promotes the pro-apoptotic p38 MAPK but not the ERK/MAPK pathway. In addition MCF-7/VDR basally contain a higher proportion of phosphorylated to total Akt, compared with parental MCF-7 cells. This may in part account for their resistance to vitamin D analogues. However, both cell lines are sensitive to the PI3K inhibitor wortmannin suggesting that even in the presence of a higher proportion of phosphorylated Akt, MCF-7/VDR cell death can be induced by blocking this cell survival pathway.

[Becky]

I have always felt strongly that high insulin levels contributed to cancer but that it could not be a surface phenomenon (due to the large molecular structure of the molecule).


Although I have not seen the study below (thanks), the clinical studies on exercise and low fat diet (of which those participants did lose an average of 7 lbs) do show that there is a significant drop in recurrence (and primarily in ER/PR neg cancers). I felt this was due to insulin levels getting lowered since ER/PR neg cancers are not dependent on hormones (which should be lower if you lose weight). However, insulin levels are lower if you lose weight and exercise (especially if you lose weight and really need to or have upper body versus lower body fat).

Thanks for the article

Becky