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17-23-david jayne


Biomedical Research 2012; 23: SI 17-23
Special Issue: Cancer Metabolism
In memory of Erich Eigenbrodt
New Horizons in Cancer Therapy: Manipulating Tumour Metabolism.
Sashidhar Yeluri, Brijesh M Madhok, David G Jayne.

Division of Clinical Sciences, Leeds Institute of Molecular Medicine, St. James’ University Hospital,
Leeds, UK. LS9 7TF, UK
Abstract
Otto Warburg first described cancers preference for aerobic glycolysis more than eight dec-
ades ago. Backed by solid data from positron emission tomography (PET) scanning, there is
now a growing body of evidence that this phenomenon provides an important metabolic dif-
ference and that this can be selectively exploited for diagnostic and therapeutic gain. Under-
standing the molecular mechanisms which underlie altered cancer metabolism may provide
us with new targets for anti-cancer therapy. In this review, we provide a brief overview of
the Warburg phenomenon together with the most likely targets for therapeutic exploitation.
In particular, attention is focused on the pyruvate dehydrogenase/pyruvate dehydrogenase
kinase system, which acts as a key regulator of mitochondrial activity and plays an impor-
tant role in the switch of metabolism from oxidative phosphorylation to aerobic glycolysis
that accompanies malignant transformation
.

Key-words: Warburg effect, Glycolysis, Hypoxia inducible factor, Pyruvate Dehydrogenase kinase,
Dichloroacetate

Introduction
The tumour microenvironment is known to be hypoxic Despite much research and the development of newer and acidotic, especially in early carcinogenesis [2-6]. The chemotherapeutic agents, the successful cure of cancer by persistent metabolism of glucose to lactate even in aero- drug therapy alone remains elusive. The main drawback bic conditions is likely an adaptation to intermittent hy- of current chemotherapy agents is the problem of prefer- poxia in pre-malignant lesions [2]. Recent evidence sug- ential tumour selectivity, with the majority of drugs hav- gests that cancer cells undertake increased glycolysis [7; ing at least a partial effect on normal cells. One area 8], secondary to an adaptive response to the hypoxic tu- where cancers show a marked difference from normal mour microenvironment, oncogenic signalling, and mito- cells is in their metabolic preferences. This difference is chondrial dysfunction. On face value, glycolysis is a very well recognised both in the laboratory as well as in clini- energy inefficient process and its preference in cancer is cal practice, as evidenced by the success of positron emis- sion tomography (PET) in evaluating solid cancers. The focus of this article is to review the existing evidence in One of the main regulatory factors promoting glycolysis support of altered cancer metabolism and to explore pos- in cancer cells is the transcription factor hypoxia induc- sible avenues for therapeutic manipulation. ible factor-1 (HIF-1), and particularly it’s α sub-unit [9; 10]. HIF-1 activates a vast array of more than 60 genes that control glycolysis, glucose uptake, angiogenesis, Warburg’s phenomenon and control of glycolysis
erythropoiesis, pH control, oxygen transport, growth fac- Most solid tumours undergo glycolysis even in the pres- tor signalling, matrix metabolism, iron metabolism, cell ence of abundant oxygen, a phenomenon first described survival and migration, and tumour growth, thus promot- by Otto Warburg in the 1920s [1], and hence aptly named ing aggressive tumour behaviour [11-13]. HIF-1 plays a the Warburg’s phenomenon or otherwise “aerobic glyco- critical role in tumour glycolysis, as it transcriptionally lysis”. There are two principal components to Warburg’s activates all glycolytic enzymes with the exception of phenomenon: i) promotion of glycolysis, and ii) down- phosphoglycerate mutase (PGAM) [14]. There is also regulation of mitochondrial respiration. evidence that HIF-1α activates pyruvate dehydrogenase Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) 17 kinase-1 (PDK-1) and PDK-3 [15-17], which are key en- tecan(53). Topotecan is approved by FDA as second-line zymes regulating the pyruvate dehydrogenase complex chemotherapy in patients with small-cell lung cancer or (PDC). PDC is known as the gate keeper enzyme for mi- ovarian cancer. Currently, there is a phase I clinical trial tochondrial respiration, regulating the flow of pyruvate investigating another HIF-1α inhibitor, PX-478, in pa- into the citric acid cycle. There is growing evidence dem- tients with advanced solid tumours or lymphomas onstrating increased HIF-1α protein expression in a wide (NCT00522652). Interestingly, Digoxin, a well-known range of primary and metastatic human cancers, with a cardiac glycolyside, has been found to inhibit HIF-1α pro- positive correlation to aggressive tumour behaviour and tein synthesis, and increases latency and reduces tumour growth in mice bearing human tumour xenograft [54]. A phase II study evaluating the addition of digoxin to er- The down-regulation of mitochondrial respiration that lotinib in non-small cell lung cancer is currently under- occurs with malignant transformation leads to aerobic glycolysis, which imparts an apoptotic resistance to can- cer cells [30]. This is linked to the down-regulation of the Pyruvate dehydrogenase complex and glycolytic control
tricarboxylic acid (TCA) cycle, which would normally Alteration of PDC complex activity, as the gate-keeper to produce reactive oxygen species (ROS) that in turn can mitochondrial activity, is another attractive therapeutic induce apoptosis in the absence of an abundant oxygen option. PDC is regulated by the inhibitory effects of a supply. The intrinsic mitochondrial membrane potential family of kinases (PDK1-4) and activated by pyruvate (∆Ψm) is much higher in cancer cells compared to normal dehydrogenase phosphatase (PDP). Four genes have been cells [31] and the hyperpolarised intrinsic mitochondrial identified in the human genome that encode the four iso- forms of PDK: isoforms 1, 2, 3, and 4 named in the order that they were first cloned [55-57]. PDK2 is the dominant Potential strategies to manipulate glycolysis
isoform as it is expressed in most organs and tissues. It There is increasing interest in bioenergetics as a means responds to the energy state of the cell [58], and thus con- for identifying new metabolic targets for cancer treatment tributes to short term regulation. Long term regulation is {for reviews [34-40]}. The Warburg phenomenon in par- achieved through the actions of PDK4 [59], another iso- ticular presents several new opportunities; it is considered form which is again expressed in most organs and tissues. to be the ‘Achilles heel’ in metabolic control of cancer, PDK4 gene is up-regulated during and after exercise in and lends itself most readily to therapeutic manipulation. There are three potential strategies for therapeutic ma- nipulation of the glycolytic pathway: i) direct inhibition Although PDK1 and PDK3 demonstrate more limited by targeting key enzymes in the glycolytic pathway, such tissue expression, the influence of PDK1 is probably not as Hexokinase, Phosphofructokinase, and Pyruvate as limited as first thought. PDK1 expression is found in Kinase (figure IA), ii) inhibition of key upstream players, heart, pancreatic islets and skeletal muscle (review, [61]. such as HIF-1α, to eliminate their influence on glycolytic Recent evidence suggests expression in lung, laryngeal enzymes (figure IB), and iii) promotion of oxidative cartilage, and tonsillar lymphoid tissue [62; 63]. PDK3 phosphorylation to force cancer cells into mitochondrial expression is restricted to testis, kidney and brain (review, respiration under inappropriate conditions and thus induce [61]. Our own work (unpublished data) confirms PDK1 expression in normal colorectal epithelium and colorectal cancer, with aberrant expression of PDK3 in colorectal Inhibiting key enzymes of the glycolysis pathway has cancers, a finding that has been recently reported [64]. shown promising results in pre-clinical studies, and some PDK1 over expression has been demonstrated in non- of the inhibitors are now in clinical trials [41; 42]. In par- small cell lung cancers [63], gastrointestinal adenocarci- ticular one of the hexokinase inhibitors, Lonidamine, has nomas [65], and head and neck squamous cancers been approved in certain chemotherapy protocols in (HNSCC) [62]. Selectively blocking HIF-1 induced up- regulation of PDK1 causing activation of PDC, which in turn induces apoptosis in cancer cells [15,17]. PDK1 and Direct HIF-1α inhibition impairs tumour growth and pro- PDK3 knockdown results in restoration of mitochondrial longs survival in experimental and animal models [48- respiration and inhibition of hypoxia induced cytoplasmic 50]. Topotecan inhibits HIF-1α translation by a DNA glycolysis and cell survival [16,66]. Likewise, PDK2 damage-independent mechanism and has been shown to knockdown reduces ∆Ψm, increases mitochondrial ROS, be beneficial in pre-clinical models [51]. The addition of increases apoptosis and decreases proliferation in cancer topotecan to bevacizumab significantly inhibited tumour cells [67]. PDK3 expression also correlates negatively growth and proliferation, and resulted in increased apop- with disease free survival in colorectal cancers (unpub- tosis in mouse xenograft [52]. A recent pilot study dem- lished data, [64]. Thus PDK isoforms offer a hitherto un- onstrated decreased HIF-1α expression in patients with explored target for selectively targeting cancers altered advanced solid tumours following use of oral topo- 8 Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) IA. Inhibition of key
Glycolytic enzymes
IB. Inhibition of
upstream players

IC. Modulation of
mitochondrial respiration


Figure I. Potential strategies for therapeutic manipulation of the glycolytic pathway: A) direct inhibition of key en-
zymes in the glycolytic pathway, such as Hexokinase, Phosphofructokinase (PFK), and Pyruvate Kinase (PK) or down-
stream players like Lactate Dehydrogenase Kinase5 (LDH5). B) Inhibition of key upstream players, such as HIF-1α, to
eliminate their influence on glycolytic enzymes. C) Promotion of oxidative phosphorylation to force cancer cells into
mitochondrial respiration.

Pyruvate
Cyt c /AIF
(C) cell membrane

Figure 2. PDK inhibition activates PDH, promotes oxidative phosphorylation, and induces apoptosis in cancer cells
by activation of proximal mitochondrial and distal NFAT-Kv pathways:
(A) Inhibition of PDK, e.g. with DCA, acti-
vates PDH and promotes conversion of pyruvate to Acetyl-coA, which subsequently enters TCA cycle and undergoes
oxidative phosphorylation. (B) This reduces the elevated mitochondrial membrane potential (∆
Ψm), and reopens the
mitochondrial transition pores. Thus, pro-apoptotic factors, e.g. cytochrome c / AIF, are released from the mitochon-
dria. (C) ROS, produced as a by-product of oxidative phosphorylation, activate redox-sensitive Kv channels on the
plasma membrane. This drops [K+]i and activates Caspases. Because of K+ efflux, the plasma membrane is hyperpolar-
ised and Ca++ channels close. This reduces [Ca++]i, inhibits Ca++ dependent transcription factor NFAT, and hence re-
duces transcription of anti-apoptotic bcl-2.
Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) 17


Dichloroacetate as a glycolytic inhibitor

colorectal cancer cells to radiation induced cell death in Dichloroacetate (DCA) is a well known PDK inhibitor. It vitro, possibly due to its effects on cell cycle. thus indirectly activates PDH and promotes glucose oxi- dation. By promoting pyruvate transport through mito- The mode of action of DCA involves two complementary chondrial respiration, it has the effect of reducing lactic mitochondrial and plasmalemmal pathways (Figure II). acid production [68; 69], an attribute which has been put The mitochondrial pathway results from increased PDH to good effect in clinical practice for the treatment of activity and mitochondrial respiration (Figure IIA). This congenital or acquired lactic acidosis [70; 71]. DCA re- leads to decreased ∆Ψm with ROS release and apoptosis duces blood glucose levels in hyperglycaemia by stimu- through activation of caspase pathway (Figure IIB) [67]. lating peripheral glucose oxidation and glycogenesis. It The plasmalemmal pathway involves the upregulation of has been demonstrated to have significant hypoglycaemic Kv1.5 channels by ROS resulting in expulsion of potas- effects in patients with type II diabetes mellitus [72]. sium ions, decreased intracellular potassium, membrane DCA also modulates fatty acid and amino acid metabo- hyper-polarization and decrease in calcium entry. This lism. In vivo experiments show that DCA impairs oxida- ultimately leads to caspase activation (Figure IIC) [67]. tion of short and medium chain fatty acids, perhaps by Wong et al. suggested that DCA induces apoptosis via the inhibiting acyl CoA synthetases [73]. Contrary to this, mitochondrial pathway by inducing expression of p53 DCA treatment resulted in significantly lower cholesterol upregulated modulator of apoptosis (PUMA) [79]. Cur- and low density lipoprotein levels in patients with hyper- rently, there are three on-going phase I/II clinical trials cholesterolemia, even in refractory cases [72,74]. DCA evaluating the role of DCA in patients with recurrent impairs oxidation of branched chain amino acids and in- and/or metastatic solid tumours, glioblastoma multiforme, creases their levels in circulation. It has an inotropic ef- and malignant gliomas (NCT00566410, NCT00703859, fect on the heart, and increases cardiac output in certain and NCT00540176). There is also anecdotal clinical evi- hypotensive patients with lactic acidosis [73]. It may im- dence supporting a role for DCA in advanced malignan- prove efficiency in ischaemic cardiac myocytes, by pro- moting glucose oxidation in conditions with limited sup- ply of high energy substrates and oxygen. For these rea- Conclusion
sons, it is an investigational drug in myocardial ischemia In conclusion, selective targeting of the glyco- lytic/mitochondrial pathway looks promising and possibly Although DCA is a non-specific inhibitor of PDK [78], holds the key to metabolic control of cancer in the future. the four isoenzymes of PDK vary in their efficacy to in- Further work is required to elucidate the aberrant expres- hibit PDH and their sensitivity to DCA. The highest inhi- sion of specific PDK isoform in various cancers. Devel- bition constant (Ki) is for PDK3 (8.0 mM) which is up to opment of selective PDK isoform inhibitors may hold the 40 times higher than the Ki for PDK 1, 2 and 4 (0.2 to 1.0 key to a successful therapeutic strategy either as mono- therapy, or in combination with established radiotherapy DCA has recently been shown to reduce growth of lung, endometrial, neuroblastoma, and breast cancer cell lines [67,79-81]. Our group has investigated the role of DCA in colorectal cancer cell lines. 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