182
Cancer Chemotherapy, Theoretical Foundations of
that are too high for clinical application,
the derivative 17-allylaminogeldanamycin
(17AAG) exhibits improved efFcacy, and
has now reached phase I clinical trials.
In the clinical setting, if cytostasis were
to be the primary outcome of treating
a patient with an Hsp90 inhibitor, then
sustained chronic administration of the
drug may not be possible because of the
associated toxicity proFle. Conversely, if
Hsp90 inhibition causes apoptosis upon
short administration, then efFcacy with
limited toxicity may be achievable. As sug-
gested by Neckers, this situation may be
solved eventually by proFling the patient’s
tumor for the nature and expression level
of Hsp90 client proteins. Combined with
further information on the appropriate
clinical schedule for Hsp90 inhibitors,
it may be possible to identify and treat
those tumors that will preferentially en-
ter apoptosis upon inhibition of Hsp90
activity. This general principle could be
important for other new agents, such as
HDAC inhibitors.
9
Blocking Angiogenesis Through Inhibiting
HIF1 Activity
Hypoxia-inducible factor 1 (HI±1) plays an
important role in regulating angiogenesis
by controlling the expression of genes link-
ing vascular oxygen supply to metabolic
demand. Tumor progression is associated
with higher levels of vascularization that
results from the increased synthesis of
proangiogenesis factors
and
decreased
synthesis of antiangiogenic factors, and an-
giogenesis progresses hand-in-hand with
the adaptation of tumor cells to growth in
low oxygen levels, by increasing glucose
transport and glycolysis. HI±1 controls the
activity of a variety of genes involved in
these processes; for example, the gene for
vascular endothelial growth factor (VEG±),
which is required for tumor angiogene-
sis, is regulated by HI±1. Similarly, target
genes include glucose transporters GLUT1
and 3, together with enzymes involved in
glycolysis like aldolase A and C, enolase 1,
and hexokinase 1 and 3.
In cells, HI±1 exists as a heterodimer
composed of HI±1
α
and HI±1
β
;HI±1
β
is
constitutively expressed, whereas HI±1
α
is
maintained
at
low
levels
in
most
cells under normoxic conditions. While
HI±1
α
is regulated through a multi-
step process, a key event involves the
hydroxylation of speciFc residues in an
oxygen-dependent manner (±ig. 6). The
modiFcation of two prolyl residues (P402
and P564) mediates the binding of the
von Hippel-Lindau (VHL) protein, which
is the targeting component of an E3 ubiq-
uitin ligase that confers degradation on
HI±1 through the proteasomal pathway.
In hypoxic conditions, prolyl hydroxy-
lation becomes rate limiting, allowing
HI±1
α
to escape degradation to favor in-
creased levels of HI±1
α
.±u
r
the
r
,Lando
et al. identiFed a second hydroxylation-
dependent control process occurring in the
C-terminal transcriptional activation do-
main, where an asparagine residue (N803)
is hydroxylated by an asparaginyl hydrox-
ylase, which blocks the interaction with
the p300 co-activator, again downregu-
lating HI± activity (±ig. 6). Collectively,
HI±1
α
activity is regulated by a series of
oxygen-dependent posttranslational mod-
iFcations mediated by three prolyl hy-
droxylases and one or more asparaginyl
hydroxylases.
Increased activity of the HI± pathway is
seen in many tumor types, resulting from
the intratumoral hypoxia together with ge-
netic alterations that affect HI±1 control.
The impact of genetic alterations on the
previous page 856 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 858 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off