A discovery by Czech molecular geneticists
Some scientists compare the search for an effective medicine against cancer, which would besides the successful elimination of cancer cells if possible not have any, or at least minimal, side effects for the organism, to the search for the Holy Grail. Unlike Indiana Jones, who in the film The Last Crusade actually found the Holy Grail, the scientific community had not had such luck as of yet. A distinct shift towards this dreamt-of goal could be the discovery by researchers from the Institute of Molecular Genetics of the Academy of Sciences of the ASCR, which was published recently in the online version of the international journal Apoptosis (see the abstract).
In 1996, the discovery of the protein TRAIL, which functions as so-called “death ligand”, i.e.
protein that after binding to the relevant receptor on the surface of a sensitive cell triggers a
complex signalling leading to the programmed cell death, apoptosis, became a hope in the treatment
of oncological diseases. TRAIL is expressed by cells of the immune system and and among other
functions also participates in anti-cancer immunity. TRAIL binds to two types of receptors, to
pro-apoptotic, from which the signal then can lead to the induction of cellular death, and to
anti-apoptotic, decoy receptors.. The sensitivity of the cells to TRAIL is regulated by relative
expression of its receptors and by the fine balance between pro- and anti-apoptotic proteins inside
the cell.
The initial experiments have shown that TRAIL can selectively kill cancer cells, whereas
normal cells are generally resistant to TRAIL-induced apoptosis. Over time, however, the
researchers discovered, that even many primary, tumour-derived cancer cells are resistant to TRAIL
and that in some of them TRAIL can even induce their proliferation and migration. They then focused
their attention on seeking an aid, which would support the unique ability of TRAIL to selectively
kill cancer cells. There are many currently used therapeutics or natural substances, which like
TRAIL can destroy cancer cells but similarly to TRAIL, cancer cells became in time resistant to
them. uA suitable combination of these substances, which would complement one another, would then
increase the chances for a successful treatment of some cancer diseases.
Scientists from the Institute of Molecular Genetics of the Academy of Sciences of the ASCR have also identified one such substance. They tested
2,448 chemical compounds in combinations with a molecule of TRAIL on a cell line coming from a
tumour of the large intestine, which is resistant to TRAIL-induced apoptosis. They achieved the
best result with homoharringtonine (HHT). It is an alkaloid, which comes from Cephalotaxus
harringtonia (the Japanese Plum Yew), a conifer from Japan. It is used in traditional Chinese
medicine for the treatment of various diseases and its synthetic form was approved in 2012 for the
treatment of adult patients with some types of chronic myeloid leukaemia.
Scientific teams under the leadership of Dr. Ladislav Anděra and Dr. Petr Bartůňek from the
Institute of Molecular Genetics of the Academy of Sciences of the ASCR have shown that the cultivation of cells from cancer of
the large intestine with TRAIL along with homoharringtonine led to their total elimination, whereas
normal cells coming from the epithelium of a healthy intestine remained resistant to this
combination and survived. The researchers have described the way homoharringtonine influences
TRAIL-induced signalling. HHT does not modulate expression of TRAIL receptors on the cell surface,
but it blocks the production of anti-apoptotic proteins, which otherwise hinder TRAIL-induced
pro-apoptotic signalling. What is also important is that the combination of HHT with TRAIL
eliminated cancer cells not only in cell cultures but also suppressed their growth in mice
harbouring tumours derived from these cells. During the 18 days after the application of the
mixture of TRAIL and HHT, tumour growth stopped and the mice did not show any signs of suffering or
other side effects.
The discovery of homoharringtonine as an aid to TRAIL in the battle with cancer cells opens
new possibilities in the treatment of cancerous diseases with a smart combination of this ligand
and other drugs or natural substances. The name of TRAIL itself, which means a path, can thus also
serve as a symbol of the path leading possibly to that oncological “Holy Grail”.
Published article:
Beranova
L,
Pombinho
AR,
Spegarova
J,
Koc
M,
Klanova
M,
Molinsky
J,
Klener
P,
Bartunek
P, Andera L. The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant
human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms.
Apoptosis. 2013
Jun;18(6):739-50
Contact:
RNDr. Ladislav Anděra, CSc., Institute of Molecular Genetics of the ASCR, tel: 241 062 471,
e-mail:
ladislav.andera@img.cas.cz;
http://www.img.cas.cz/research-groups/ladislav-andera/
3 Jun 2013
