Systems Biology Approaches to Cancer Energy Metabolism - Systems Biology of Metabolic and Signaling Networks - page 210

9.2 Inhibiting Tumor Glycolysis

In most tumor cells the glycolytic flux is 2- to 17-fold higher compared to normal
cells as a consequence of the over-expression of all the glycolytic enzymes and
transporters induced by several oncogenes and the hypoxia-inducible factor-1
(HIF-1). This results in the excretion of large amounts of lactate even under aerobic
conditions, a phenomenon known as the “Warburg effect” of cancer cells (reviewed
by Moreno-S´nchez et al. 2007 ; Mar´n-Hern´ndez et al. 2009 ). It is worth recalling
that in addition to contributing to the ATP supply for cellular work, the increased
rate of tumor glycolysis also provides various glycolytic intermediaries which are
precursors for the synthesis of macromolecules (polysaccharides, nucleic acids,
triglycerides, proteins) required for the constant and accelerated cell proliferation.
Moreover, an increased glycolysis may predominate for ATP supply when
mitochondria are damaged (Carew and Huang 2002 ) and an active mitochondrial
degradation (mitophagy) occurs (Lock et al. 2011 ) or when tumor cells are under
hypoxic conditions (Xu et al. 2005 ). In addition, a correlation between increased
glycolysis and tumor resistance to chemo- and radiotherapy has been found
(Fanciulli et al. 2000 ; Maschek et al. 2004 ; Xu et al. 2005 ; Lee et al. 2007 ).
Therefore, it has been suggested that inhibition of this essential pathway might be
a therapeutic option to increase the effectiveness of chemotherapy and radiotherapy
(Pelicano et al. 2006 ).
The effect of individual inhibition of various glycolytic enzymes (hexokinase II,
HKII; phosphofructokinase type 2 B3, PFKFB3; glyceraldehyde-3-phosphate
dehydrogenase, GAPDH; lactate dehydrogenase A, LDH-A) or transporters (glu-
cose transporter 1, GLUT1; monocarboxylate transporters, MCT) on tumor survival
has been evaluated using a great variety of inhibitors (Pedersen et al. 2002 ; Pelicano
et al. 2006 ; Kumagai et al. 2008 ; Bartrons and Caro 2007 ; Evans et al. 2008 ; Clem
et al. 2008 ) with poor outcomes. In general, in such studies the targets have been
chosen somewhat randomly and arbitrarily: most research groups focus on targeting
the presumed rate-limiting steps reported on biochemistry textbooks (HK; phos-
phofructokinase type 1, PFK-1; pyruvate kinase, PYK), while others have used
molecular biology tools (knock-down by RNAi, siRNA) to identify the essential or
“key” enzyme (hexosephosphate isomerase, HPI; HKII, PYKM2, LDH-A)/
transporter (GLUT1) for tumor growth (Funasaka et al. 2007 ; Amann et al. 2009 ;
Zhou et al. 2010 ; Kim et al. 2011 ; Goldberg and Sharp 2012 ). However, drug target
validation studies suggest that an almost complete pharmacological inhibition is
required in order to obtain similar decreases in flux and pathway function to those
reached by the genetic knockout of the pharmacological target; however, the use of
elevated drug doses promotes toxic side effects in the host. Therefore, promising
drug targets should be those enzymes/transporters for which a lower inhibitor dose
suffices to produce a major effect on the pathway flux (flux-control) and/or the
metabolite concentrations (homeostatic control). Otherwise stated, the steps that
should be targeted are those controlling the pathway function (reviewed in
Hornberg et al. 2007 ; Hellerstein 2008 ; Moreno-S´nchez et al. 2010 ).