Withaferin A inactivates the oncogenic kinases PAK1 and AKT.

An extract from Ashwagandha (roots or leaves), so-called "Indian Ginseng",
has been used as a Indian traditional herbal medicine (Ayurveda) to treat
several diseases including cancer and inflammation. According to a recently
study by Renu Wadhwa's group at AIST in Japan, the alcoholic extract containing
the anti-cancer steroid "Withaferin A" (WA) inhibits the growth of glioma cells
and their migration/metastasis. It is also known that the WA strongly
inhibits the angiogenesis and inflammation. These observations altogether
strongly suggest, if not proved as yet, that this extract contains an anti-PAK1
ingredient(s), because the oncogenic kinase PAK1 is essential for the growth
of more than 70% of human cancers including glioma, angiogenesis, and metastasis,
as well as inflammatory diseases such as asthma and arthritis.

If so, since WA passes the BBB (blood brain barrier), this extract or WA,
could be potentially useful for the treatment of PAK1-dependent formidable
brain tumors such as glioma, NF (neurofibromatosis) and TSC (tuberous sclerosis)
for which no FDA-approved effective therapeutic is available on the market
as yet, although the NZ propolis extract "Bio 30", a natural anti-PAK1 product
available on the market inexpensively, has been proven to be quite effective
in suppressing the growth of human NF tumors (both NF1 and NF2) and glioma,
as well as pancreatic and breast cancers, in mice, and is currently in trials
for the treating these tumor patients.

Interestingly, in 2007 by Ping Dou's group at Karmanos Cancer Institute
in Detroit, WA (4-8 mg/kg, daily) was found to inhibit the 26S proteasome
of human (PTEN-deficient) prostate cancer (PC-3) xenografts in mice, thereby
inhibiting their growth by 54-70%. Among the proteasome targets, a few tumor
suppressors including p27 and p21, two CDK inhibitors, are significantly
stabilized (accumulated) by WA treatment. Interestingly, p27 is down-regulated
by the oncogenic kinase AKT, whereas p21 is down-regulated by PAK1. In other
words, WA clearly inactivates both AKT and PAK1, suggesting that WA probably
stabilizes the tumor suppressor PTEN, a target of 26S proteasome, just as
does thalidomide (as mentioned previously).

The WA content in Ashwagandha leaves, which is much higher than that in roots,
is 1-2% (10-20 mg/g) depending on the species. Thus, the effective daily
dose of this leave extract could be around 500 mg/kg, if no other ingredient
in this extract enhances the anti-cancer activity of WA. However, the recent in vitro study
by the AIST group suggests otherwise: IC50 of WA alone and the extract
for glioma cell growth appear to be basically same (around 1 micro g/ml).
In other words, the anti-cancer activity of WA might have been boosted
50-100 times by a few other ingredients of this extract.

Furthermore, this extract at the dose (100 mg/kg, twice a week) suppresses
the growth of human fibrosarcoma (HT1080, carrying the oncogenic N-RAS mutant)
xenograft in mice by more than 50%, while WA at the dose (10 mg/kg,
twice a week) has little effect on the tumor growth.
Most surprisingly, the major anti-cancer ingredient in this extract turned out
to be "Withanone", instead of WA.

Thus, it would be worth determining the effective dose of this extract
on the growth of human glioma or NF tumor xenograft in mice as well.