Rangaprasad Sarangarajan
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Intracellular signaling occurs through cascades of
interconnected/interdependent networks, rather than through linear
pathways. Because effector molecules modulating this network typically
function in both redundant and pleiotypic fashion, selective modulation of
a single intracellular signaling pathway seems highly improbable. The
desirable objective of targeting a specific signaling pathway for
potential therapy is based on the assumptions that (a) selective
modulation of a single (disease causative) pathway and/or molecule will
result in negligible side effects and (b) a single molecule can
selectively block a single (specific) signaling pathway.
That these assumptions may not necessarily be true is exemplified by
the recent recall of the cyclooxygenase-2 (COX-2) inhibitor Vioxx™
(Merck, Whitehouse Station, New Jersey, USA). Selective blockade of COX-2
results in COX-1 mediated increase in the ratio of thromboxane (an
endothelial vasoconstrictor and agonist for platelet aggregation) to
prostaglandin I2 (an endothelial vasodilator and platelet aggregation
antagonist) and may be one of the many reasons for the observed increase
in the incidence of cardiac related events in patients taking Vioxx.
The scientific literature is replete with examples of such egregious
"cross talk" even among pathways with functions that seem
diametrically opposite, making it practically impossible to block a single
pathway with just one molecule without affecting other pathways; as a
corollary, it necessitates that one molecule should possess myriad
pharmacological effects. Alternatively, a number of molecules might be
required to block specific sections upstream or downstream of signaling
junctions where different pathways meet.
Abnormal expression patterns of receptors, enzymes or mutant proteins
(by themselves or in combination) appear to be optimum targets for
modulating specific signaling pathways to alleviate symptoms. Thus, in
chronic myelogenous leukemia (CML), Gleevec's (Novartis Pharmaceuticals
Corporation, East Hanover, New Jersey, USA) target — the mutant protein
p210BCR-ABL, arising from a reciprocal chromosomal rearrangement —
essentially defines the disease it was designed to treat. In contrast, in
the absence of well-defined molecular etiopathology of disease or in
situations where the molecular phenotype is less accurate in prediction of
a clinical response, the rationale to target specific signaling pathways
cannot be justified and is often not efficacious.
A major component of extracts/decoctions of natural products are
glycosides, the aglycone portion comprised of terpenes, phenolic flavones,
anthraquinones or tannins, which display varying degrees of anti-oxidant
properties. Since the redox status of a cell is an established generic
mechanism that can modulate multiple signaling pathways, these extracts
are likely to exert their pharmacologic effects by modulating many such
pathways in unison. The antioxidants in this "evolutionary
cocktail" could represent effective up-regulators or down-regulators
of multiple pathways or specific sections of these pathways involved in
"cross talk" with the (disease) causative pathway, such that
when administered together they produce the desired pharmacologic effect
with minimal side effects. For example, curcuminoids present in turmeric
not only are potent inhibitors of COX-2 but also inhibit platelet
aggregation via the thromboxane pathway.
It would be ironic if multiple signaling pathways were found to be
modulated in a similar fashion by an optimized "cocktail" of
synthetic drugs and ancient herbal recipes. The reductionist single-gene
or protein-centric paradigm common in current biological research may need
to be modified into a network-centric approach with the added recognition
that a majority of disorders are probably polygenic, with substantial
environmental and epigenetic components. The magic "shotgun" may
prove more efficacious and safer than the magic "bullet."
Editor's note: Debuting this month, our "Voice of
Discovery" column offers an opportunity for readers to voice their
opinions, on any number of topics, to the drug discovery community. To
respond to this installment, or to submit a guest editorial of your own,
contact Douglas McCormick, Editor-in-Chief at dmccormick@advanstar.com
Rangaprasad Sarangarajan is assistant professor of pharmacology
and toxicology at Massachusetts College of Pharmacy and Health Sciences. Shireesh
Apte (not pictured) is a scientist at Baxter IV Systems in Murray
Hill, New Jersey, USA. Rangaprasad Sarangarajan can be reached at
Massachusetts College of Pharmacy and Health Sciences, School of
Pharmacy—Worcester, 19 Foster Street, Worcester, MA 01608. E-mail ranga.sarangarajan@wor.mcphs.edu
