Biomedical Engineering Reference
In-Depth Information
carcinogenic process, such as cell proliferation, resistance to apoptosis, cell migra-
tion or invasiveness [
83
,
84
,
228
,
229
]. In fact, the expression of these channels is
often altered in human cancers, as demonstrated by the biopsies of many epithelial
tumors, where an overexpression of VGSCs has been found [
230
-
233
].
The use of VGSC blockers in the treatment of cancer appears to be very
promising, especially considering the advantages of this therapy. In fact, they
often act extracellularly, thus having limited metabolic effects and allowing an
easier calibration of the treatment, together with an easier ability to test different
structures in vitro [
83
]. Some examples of sodium channel inhibitors proven to
affect tumor progression are the neurotoxin TTX that inhibits cell invasion in vitro
in breast and prostate cancer cell lines, and phenytoin and
a
-hydroxy-
a
-
phenylamides (Figs.
3
and
8
), useful to treat prostate cancer by inhibiting cell
proliferation [
234
-
239
]. However, it is difficult to imagine the use of an existing
sodium channel blocker to treat cancer, because many of them (i.e., anticonvulsants
or antidepressants) can cross the blood-brain barrier and almost all the small
molecules so far known do not have selectivity between the different isoforms,
thus causing many side effects. The main goal for the treatment of cancer by using
sodium channel interfering drugs will be the discovery of new subtype-specific
blockers, especially acting on the Na
V
1.5 or Na
V
1.7 isoforms, thus able to treat the
disease though avoiding the occurrence of undesired side effects.
4 Conclusion
As indicated in the chapter, there is a wide range of VGSC pathologies, caused by
mutations in sodium channel genes, bringing to altered function of membrane ion
channels. The VGSC blockers, historically used to treat epilepsy, are now
employed also for the treatment of other diseases, although with the consequence
of many adverse side effects. As a matter of fact, these drugs are not able to
discriminate between different channel subtypes, due to a high degree of sequence
homology between them. Nevertheless, it has been proved that AEDs do not have
serious side effects, for example, on the heart, and this is due to the existence of a
state- and use-dependent block caused by certain small VGSC blockers. The design
and synthesis of selective molecules will increase the therapeutic utility of VGSC
modulators, especially considering that it is now possible to associate channel
subtype mutations to specific disorders (i.e., Na
V
1.5 in cardiac dysfunctions,
Na
V
1.7 in pain). In the last years, many new molecules have been designed with
the aim to obtain subtype selective VGSC blockers, and to avoid the side effects
affecting the safety profiles of nonselective drugs. Some among those compounds
are now in clinical trials for the treatment of various disorders.
Certainly, Accademia and pharmaceutical industry have a great degree of
interest in the search of new VGSC blockers, as demonstrated by the huge number
of articles and patents published on this topic. In fact, it is now clear that VGSC
modulators are endowed with an enormous and multifarious therapeutic potential.
