Therapeutic Hope for TSC (Tuberous Sclerosis) Patients

A complex disease called TSC (Tuberous Sclerosis) is caused by deletion or dysfunction of either TSC1 or TSC2 genes. Both gene products are tumor suppressors which form a complex that normally serves as a GAP (GTPase activating protein=attenuator) of a GTPase /G protein called Rheb. Thus, in TSC patients, Rheb is abnormally activated (becoming oncogenic!), and then activates another kinase "TOR" that in turn activates the potentially oncogenic S6 kinase. Thus, in many cases TSC is associated with a variety of tumors, which mainly develop in brain, spleen and kidney. Since these tumors very often develop in a quite early stage of life, most of TSC patients' life span is significantly shorter than non-TSC people's. Unfortunately, so far no effective (FDA-approved) therapeutic is available on the market. However, since "TOR" (target of rapamycin) could be effectively inhibited by the antibiotic "Rapamycin" or its more potent derivative "CCI-779" in rodent TSC models (1), in the future (in several years, hopefully) when clinical trials of "CCI-779" are successfully completed for the approval by FDA, the anti-cancer drug "CCI-779" will become available for the treatment of TSC and other formidable tumors.

Of course, many TSC patients, in particular parents of TSC children, often asked me if there is any effective "alternative" (non-FDA-approved) medicines or natural products which would be helpful for improving the conditions of TSC patients. In the past, until very recently, sadly I had to answer nothing but "No". However, eventually this year, I would be able to say to these TSC patients, "YES, YOU CAN have a specific alternative medication. There are a few potentially effective natural anti-PAK products on the market which would be helpful for TSC and other formidable diseases such as NF (neurofibromatosis) ". I will tell you how the situation has been dramatically changed. It has nothing to do with Barack Obama's new administration at the White House, but a few dedicated bio-medical scientists discovered something useful for the therapy of TSC patients.

The kinase "PAK" is essential for the growth of more than 70% of cancers and NF tumors, and therefore we have developed a series of anti-PAK drugs (synthetic chemical compounds) and also identified several anti-PAK natural products available on the market inexpensively, such as NZ propolis extract called "Bio 30", curcumin, ivermectin, and vitamin K2 (menaquinone-7) from "Natto", for these PAK-dependent tumors.

Interestingly, this year, a few scientific groups began providing an evidence suggesting that TSC tumors appear to be among these PAK-dependent tumors. First of all, curcumin, a yellow spice in Indian curry, inhibits PAK directly (2). Secondly, curcumin blocks the Raptor-TOR interaction (3). Raptor is a protein essential for the oncogenicity of TOR, and therefore, curcumin could block the oncogenic TOR signaling in TSC tumors. However, the bioavailability of curcumin alone is very poor (mainly due to water-insolubility), and without liposome or CD (cyclodextrin) which would solubilize curcumin, curcumin alone won't be effective for clinical application.

However, Bio 30, which is a water-miscible extract, and "Natto", a fermented sticky soybean product, which has been a traditional Japanese cuisine for a thousand years, would be effective for the treatment of both NF and TSC tumors as well as several PAK-dependent cancers such as pancreatic, colon, breast and prostate cancers as well as glioma, melanoma and MM (multiple-myeloma).

Also around two years ago, it was found that PAK inactivates the tumor suppressor "FOXO" that normally suppresses "Raptor" gene (4-6). In other words, these natural anti-PAK products on the market inactivate "TOR" by down-regulating "Raptor" in TSC tumors. Thus, I am now pretty convinced that TSC tumors could be treated with these anti-PAK products, as NF tumors.

Currently more than 150 NF patients are in my trials of Bio 30 world-wide, and we would welcome any TSC patients to join my trials. The recommended daily dose of Bio 30 (alcohol-free liquid) is 1 ml per 10 kg of body weight, and it costs only a dollar or so for the daily treatment. It causes no side effect, except for an allergic skin reaction which occurs only in 1% of population, due to its CAPE (caffeic acid phenethyl ester) which is the major anti-PAK ingredient (7).

If you wish to order Bio 30 (25 ml bottles) at NF/TSC discount price by joining my trials, please contact directly Annette Rea of Manuka Health, NZ: Annette@manukahealth.co.nz


References:

1. Lee, L., Sudentas, P., Donohue, B., Asrican, K. et al. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005, 42, 213-27.

2. Cai, XZ., Wang, J., Li, XD., Wang, GL.et al. Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression. Cancer Biol Ther. 2009, 8, 1360-8.

3. Beevers, C., Chen, L., Liu, L., Luo, Y. et al. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res. 2009, 69, 1000-8.

4. Maruta, H. An innovated approach to in vivo screening for the major anti-cancer drugs. In “Horizons in Cancer Research” 2010: 41 (ed. Morrison, EP), pp249-59, Nova Science Publishers.

5. Jia, K., Chen, D., Riddle, D. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004, 131, 3897-906.

6. Southgate, R., Neill, B., Prelovsek, O., El-Osta, A. et al. FOXO regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem. 2007. 282, 21176-86.

7. Demestre, M. Messerli, S., Celli, N., Shahhossini, M. et al. CAPE (Caffeic Acid Phenethyl Ester)-based Propolis Extract (Bio 30) Suppresses the Growth of Human Neurofibromatosis(NF) Tumor Xenografts in Mice. Phytother. Res. 2009, 23, 226-230.


The corresponding author:

Prof. Hiroshi Maruta, Manager
NPO “NF CURE Japan”,
Melbourne, Australia.

The former head of Tumor Suppressor Lab.
Ludwig Institute for Cancer Research
(Melbourne Branch)

E-mail: maruta19420@mac.com or julie8860@gmail.com