Thalidomide: Anti-PAK/AKT mechanism underlying its anti-angiogenic, anti-inflammatory and teratogenic actions.

Thalidomide, an old pill used for morning sickness, that causes "teratogenesis"
(limb under-development ) of embryos in the womb of so many pregnant women
during 1950s, also blocks the tumor-induced angiogenesis and inflammation.
Thus, it would be potentially useful for the treatment of solid tumors and
inflammation such as arthritis in "non-pregnant" patients. However, the
molecular mechanism underlying these multi-functions of this drug remained
to be clarified until recently. In 2008, a group led by Juergen Knobloch
at Heinrich Heine University, Duesseldorf, Germany, found that this drug
stabilizes the tumor suppressor PTEN, and thereby blocking the oncogenic
kinases PAK1 and AKT, which are involved in both angiogenesis and inflammation.
as well as limb formation. Thus, like FK228, the most potent HDAC inhibitor
still in clinical trials (phase 2), that eventually activates PTEN gene,
thalidomide would be potentially useful for the therapy of these PAK1/AKT-dependent
diseases. Since this drug passes BBB (blood brain barrier), it would be
effective to suppress the growth of PAK1-dependent brain tumors such as
glioma, NF (neurofibromatosis, in particular NF2) and TSC (tuberous sclerosis)
tumors.

Interestingly, thalidomide causes teratogenesis in human, rabbit and chicken,
but never in either mouse or rat. Why? The same group found the major
reason: this drug induces the taratogenic superoxide, but in mouse and
rat cells an anti-oxidant called GSH (glutathione) is extremely abundant,
compared with human, rabbit and chicken counterparts, and bleaches the superoxide,
so that this drug fails to cause the teratogenesis (under-development of
limbs) in mouse or rat embryos. If the preclinical toxicity test of this
drug were conducted in "pregnant" chicken or rabbit, instead of "pregnant"
mouse or rat, its teratogenic effect had been found, before it was used world-
wide as a pill for pregnant women's morning sickness! Anyhow, a strong anti-
oxidant would protect embryos from the thalidomide-induced teratogenesis
(birth of so-called "angel babies").

It would be worth pointing out that a series of thalidomide derivatives have
been developed by the US company "Celgene" around 2004, and one of them
called "CC-5013" is water-soluble and non-teratogenic, although it is still
anti-angiogenic and anti-inflammatory. In other words blocking angiogenesis
alone would not cause the teratogenesis! CC-5013 is currently in clinical
trials for solid tumors such as MM (multiple myeloma) and inflammatory diseases.

Cereblon: Thalidomide's target for its teratogenesis

http://news.sciencemag.org/sciencenow/2010/03/-thalidomide-ranks-as-one.html

In March this year, a group led by Hiroshi Handa at Tokyo Institute of
Technology (TIT) in Japan, found a direct target of thalidomide that causes
teratogenesis: It is a protein called "cereblon" which is associated with
proteasome (proteolytic complex). Binding of this drug to "cereblon" blocks
the ubiquitin-dependent proteolysis of many proteins, presumably including the tumor
suppressor "PTEN". So I wonder if the non-teratogenic derivatives of thalidomide
such as CC-4047 and CC-5013 developed by "Celgene", which are currently
used mainly for the therapy of the PAK-dependent cancer "MM" (multiple myeloma)
and inflammatory diseases, no longer bind this "cereblon" or not...