Biology Reference
In-Depth Information
More recently, this effect on simple GRE-dependent transcription has been con-
firmed in leukemic cells from patients with B-cell chronic lymphocytic leukemia
(Tiwari et al.
2005
) and, of relevance to the subject of this chapter, in human
bronchial epithelial cells (Kaur et al.
2008a
). It is, perhaps, more significant that
in human acute T-lymphocytic leukemia cells, certain proapoptotic proteins (p53,
p21
WAF1/CIP1
) are also upregulated by both PDE4 inhibitors and glucocorticoids
alone and in combination leading to additive and/or synergistic proapoptotic effects
(Ogawa et al.
2002
). Thus, if these types of interactions occur in proinflammatory
and immune cells implicated in the pathogenesis of diseases such as asthma and
COPD, then PDE4 inhibition could enhance the ability of glucocorticoids to induce
anti-inflammatory genes. In addition, a potential advantage of this approach is that a
low dose of a PDE4 inhibitor, which may be subtherapeutic as a monotherapy,
could boost glucocorticoid action in the same way as a LABA. Finally, there are
data indicating that in a T-leukemia cell line, such effects are not limited to PDE4,
but also extend to inhibitors of PDE3 and PDE7 (Dong et al.
2010
), indicating
the potential for the development of additional, potentially highly effective, novel
combination therapies with which to treat chronic airway inflammation (Zhang and
Insel
2004
).
In considering the clinical utility and advantages of PDE4 inhibitor/glucocorti-
coid combination therapies over a PDE4 inhibitor alone as a monotherapy, it is
important to appreciate that many of the proinflammatory genes that may be
induced by cAMP (Ammit et al.
2000
; Hertz et al.
2009
; Holden et al.
2010
) are
likely to be repressed by glucocorticoids. Thus, a PDE4 inhibitor and an ICS given
together may be a considerably superior medicine for several reasons. First, the
cAMP signal generated in response to PDE4 inhibition may enhance the maximal
transcriptional activity of the glucocorticoid. Second, the PDE4 inhibitor will exert
anti-inflammatory activity independently of its effect on GR-mediated
trans
activa-
tion of anti-inflammatory genes. Third, the undesirable ability of PDE4 inhibitors to
induce proinflammatory genes will be negated by the glucocorticoid.
An appreciation of rate of cAMP synthesis in target tissues is also a critical
factor that will influence the efficacy of a PDE4 inhibitor. If adenylyl cyclase
activity in those tissues is low, a PDE4 inhibitor might not elevate cAMP by an
amount or at a rate necessary for its therapeutic activity to be realized. One
approach to obviate this possibility is to combine a PDE4 inhibitor/ICS combina-
tion therapy with a receptor agonist that drives cAMP synthesis. Clearly, from a
COPD perspective, a
b
2
-adrenoceptor agonist would be the obvious choice given
that both LABAs and SABAs (on an as-needed basis) are a recommended treatment
option for patients with mild disease (see O'Donnell et al.
2008
). Adding a PDE4
inhibitor to patients with severe asthma who might not be adequately controlled by
a LABA/ICS combination therapy could also afford additional benefit. Thus, a
persuasive argument can be made for the development of triple combination
therapies. Such novel medicines could also be advantageous in smoking asthmatic
individuals in whom ICSs are relatively refractory (Chalmers et al.
2002
; Thomson
et al.
2004
,
2006
; Thomson and Spears
2005
).
