Epigenetic Targets in the Treatment of cancer-Juniper Publishers
Novel Approaches in Drug Designing & Development (NAPDD)
After the identification of genetic elements in DNA
it became apparent that specific cell functions required sophisticated
mechanism to regulate gene expression [1].
This is obtained by modifications of DNA and of histones: methyl
residues can be inserted on DNA (cytidine) or on histones (lysine or
arginine), while acetyl groups on histones are added or removed to turn
genes on or off. The epigenetic machinery is very complex consisting of
different protein complexes responsible for the different steps
required: by applying a simplification that is certainly inaccurate but
useful in practical terms, proteins involved in epigenetic regulation
can be divided into writers, erasers and readers. When it was found that
these mechanisms may also be responsible for the malignant behaviour of
transformed cells [2,3] researchers started to look for specific inhibitors that could be used in the "epigenetic treatment" of patients [4].
Some drugs have long been in clinical use under a
different label: this applies to Valproic acid and to anti metabolites
such as Cytrarabine (Cytosine arabinoside), 5-aza-cytidine, and
Decitabine. Cytarabine was used according to different protocols: when
given in low, repeated doses it did not result in relevant anti
proliferative effect and it was able to induce sporadic but consistent
cases of differentiation of leukemic cells [5].
One of the advantages of these regimens was their very limited toxic
side effects which allowed prolonged and well tolerated treatment even
in elderly patients [6].
By today standards these should be considered in every respect
"epigenetic" treatments. On the other hand the term "epigenetic
treatment" could be used for any therapy that leads to reprogramming of
gene expression. All-trans retinoic acid is an exceptional example of
how malignant cells can be redirected toward physiological development
through pharmacological manipulation of gene expression [7]. In a similar way estrogens and anti-estrogens regulate gene expression through epigenetic control [8,9] and should therefore be included in this definition.
Concerning histone acetylation-deacetylation several
molecules acting on these mechanisms are now in clinical use: the first
was Valproic acid, while Belinostat, Panobinostat and Vorinostat (SAHA)
were later added to this list. Today a number of molecules acting on
similar or on different targets have been registered for clinical use,
especially in haematological malignancies [10,11], or are in different phases of clinical evaluation [12]. With reference to solid tumours we recently reviewed studies reporting on their epigenetic treatment [13].
Traditionally the biological characterization of
malignant cells is more accurate in haematology and this may at least in
part explain why epigenetic treatment is in a more advanced phase for
haematological malignancies [14].
Progress however is also being made in solid tumours: several
histological types have been carefully analysed and today a sort of
"epigenetic signature" can even be used to identify carcinomas of
unknown origin [15]. Brain tumours are among the histological types that have been studied in detail [16] and several potential epigenetic targets have been identified [17,18]. The identification of isocitrate dehydrogenase (IDH) mutations as a prognostic element [19-21]
is of particular interest. Mutated IDH can produce R
(-)-2-hydroxyglutarate which is under many aspects an "on co metabolite"
[22]. IDH role and the relevance of its mutations have been well described [23]
and since this enzyme and its products play a role in the regulation of
cell metabolism it appears that epigenetic control and energetic
metabolism are strictly related [24-28].
Conclusion
The use of molecules that interfere with the
epigenetic regulation of gene expression is a promising strategy
especially in tumour types that do not respond to traditional anticancer
agents. In order to accelerate drug development we need to identify
those tumours that have a better probability of responding. The
crossroad between epigenetics and cellular energetic metabolism is a
particularly stimulating field of research that may bring excellent
results in the future if
adequately exploited.
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