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major sources of 5
-nucleotidase may be snake venoms, particularly those from rat-
tlesnakes (genera
Crotalus
and others) [3]. It is thought that snakes utilize purines
as an effective, multifunctional means of envenomation [2].
CD73 directed therapies have not been well-developed. In our own experience,
we have documented use of the CD73 inhibitor APCP in various murine models [18,
65, 69]. APCP is well tolerated, biologically available through the oral route, and
non-toxic in mice up to 60 mg/kg/day. Interestingly, we have noticed that APCP
treatment of mice appears to promote subtle increases in aggressive behavior and
anxiety (unpublished observation). It is possible that this behavior is related to pre-
vious findings of increased aggression in adenosine A1R
-
and A2AR-deficient mice
[22, 38], and may suggest that APCP is biologically available across the central
nervous system. While many studies have suggested that adenosine is beneficial for
most host responses, there may be examples where inhibition of adenosine genera-
tion (e.g. by inhibition of CD39 or CD73) is warranted. As alluded to above, during
enteric pathogen infection, adenosine may promote water transport across intestinal
epithelia and the symptoms of secretory diarrhea. For these purposes, CD39 and
CD73 inhibitors such as POM-1 and APCP, respectively, could prove effective as
anti-diarrheals. In this same context, it is possible that pulmonary edema related to
infectious pneumonia or inflammation may benefit from the use of these inhibitors.
Studies directed at defining these principles are currently underway.
Given the established association between angiogenesis and adenosine A2 recep-
tor activation, the controlled regulation of CD39 / CD73 activity could influence
angiogenesis. It is possible, for example, that systemic administration and/or
targeting of inhibitors could prove beneficial for inhibition of tumor angiogene-
sis, currently an area of intense interest in cancer research. This is particularly
compelling given the known association between hypoxia and the tumor microen-
vironment [57], wherein hypoxia and HIF-1 activation are potent transcriptional
stimuli for CD73 expression[65] (also see above). Under such circumstances, it is
reasonable that many tumors might over-express CD73. Thus, inhibition of adeno-
sine production by CD39 / CD73 could be a therapeutic target for the prevention of
tumor angiogenesis and metastasis [6, 61, 72].
Finally, given the strong association between hypoxia/HIF and extracellular
adenosine generation, it may be possible to mimic hypoxia through pharmaco-
logic means. Of great interest in this regard are agents which active HIF, primarily
through the inhibition of HIF prolyl hydroxylases. These enzymes were identified on
the principle that other mammalian prolyl-hydroxylases such as those which target
extracellular collagen were 2-oxoglutarate-dependent [7], and it was predicted that
the HIF prolyl hydroxylases would also belong to this family of enzymes. Based on
conserved structural features [7], a candidate molecular approach was used to define
HIF-modifying enzymes. This approach identified the HIF prolyl hydroxylases as
the products of genes related to
C. elegans
egl-9, a gene that was first described
in the context of an EGg-Laying abnormal (EGL) phenotype [19]. In mammalian
cells, three PHD isoforms were identified (PHD 1-3), and shown to hydroxylate
HIF-
in vitro [27, 30]. These enzymes have an absolute requirement for oxygen as
substrate. The overall reaction results in insertion of one oxygen atom into the HIF-
α
α
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