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. We have shown that DCA Warburg O. On the origin of cancer cells. Science induces apoptosis and cell cycle arrest in cancer cells, but has no such effect in non-cancerous cells [82]. This effect Gatenby RA, Gillies RJ. Why do cancers have high appears to be independent of hypoxia. We have also aerobic glycolysis? Nat Rev Cancer 2004; 4(11): 891-9. shown that it depolarises the intrinsic mitochondrial Gatenby RA, Smallbone K, Maini PK et al. Cellular membrane in colorectal cancer cells but not in non- adaptations to hypoxia and acidosis during somatic cancerous cells [82]. A significant synergistic anti-tumour evolution of breast cancer. Br J Cancer 2007; 97 (5): effect has been demonstrated with the use of DCA and traditional 5-fluorouracil in colorectal cancer cell lines Milosevic M, Fyles A, Hedley D et al. The human tu- [83]. DCA potentiates the cytotoxicity of carboplatin in mor microenvironment: Invasive (needle) measurement lung carcinoid cell lines [84] and cisplatin in cervical can- of oxygen and interstitial fluid pressure. Semin Radiat Oncol 2004; 14 (3): 249-258. cer HeLa cells [85]. Although DCA alone produced sig- Dewhirst MW, Tso CY, Oliver R et al. Morphologic nificant cytotoxic effects, and was associated with G1 cell and hemodynamic comparison of tumor and healing cycle arrest and increased rate of apoptosis, the combina- normal tissue microvasculature. Int J Radiat Oncol Biol tion of DCA with irradiation enhanced radiation's killing effects on prostate cancer cell lines [86]. Initial results Shah-Yukich AA, Nelson AC. Characterization of solid from our work (unpublished) reveal that DCA sensitizes tumor microvasculature: a three-dimensional analysis 0 Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) using the polymer casting technique. Lab Invest 1988; 22. Aebersold DM, Burri P, Beer KT et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and Wu M, Neilson A, Swift AL et al. Multiparameter prognostic parameter in the radiotherapy of oropharyn- metabolic analysis reveals a close link between attenu- geal cancer. Cancer Res 2001; 61(7): 2911-2916. ated mitochondrial bioenergetic function and enhanced 23. Zhong H, De Marzo AM, Laughner E et al. Overex- glycolysis dependency in human tumor cells. Am J pression of hypoxia-inducible factor 1alpha in common Physiol Cell Physiol 2007; 292 (1): C125-C136. human cancers and their metastases. Cancer Res 1999; Bi X, Lin Q, Foo TW et al. Proteomic analysis of colo- rectal cancer reveals alterations in metabolic pathways: 24. Talks KL, Turley H, Gatter KC et al. The expression mechanism of tumorigenesis. Mol Cell Proteomics and distribution of the hypoxia-inducible factors HIF- 1alpha and HIF-2alpha in normal human tissues, can- Iyer NV, Kotch LE, Agani F et al. Cellular and devel- cers, and tumor-associated macrophages. Am J Pathol opmental control of O2 homeostasis by hypoxia- inducible factor 1 alpha. Genes Dev 1998; 12 (2): 149- 25. Zagzag D, Zhong H, Scalzitti JM et al. Expression of hypoxia-inducible factor 1alpha in brain tumors: asso- 10. Semenza GL. Hypoxia-inducible factor 1: master regu- ciation with angiogenesis, invasion, and progression. lator of O2 homeostasis. Curr Opin Genet Dev 1998; 8 26. Bachtiary B, Schindl M, Potter R et al. Overexpression 11. Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the of hypoxia-inducible factor 1alpha indicates diminished HIF pathway in cancer. Curr Opin Genet Dev 2001; 11 response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical can- 12. Harris AL. Hypoxia--a key regulatory factor in tumour cer. Clin Cancer Res 2003; 9 (6): 2234-2240. growth. Nat Rev Cancer 2002; 2 (1): 38-47. 27. Schindl M, Schoppmann SF, Samonigg H et al. Over- 13. O'Donnell JL, Joyce MR, Shannon AM et al. On- expression of hypoxia-inducible factor 1alpha is asso- cological implications of hypoxia inducible factor- ciated with an unfavorable prognosis in lymph node- 1alpha (HIF-1alpha) expression. Cancer Treat Rev positive breast cancer. Clin Cancer Res 2002; 8 (6): 14. Kondoh H. Cellular life span and the Warburg effect. 28. Birner P, Schindl M, Obermair A et al. Expression of hypoxia-inducible factor 1alpha in epithelial ovarian 15. Papandreou I, Cairns RA, Fontana L et al. HIF-1 medi- tumors: its impact on prognosis and on response to ates adaptation to hypoxia by actively downregulating chemotherapy. Clin Cancer Res 2001; 7 (6): 1661- mitochondrial oxygen consumption. Cell Metab 2006; 29. Birner P, Gatterbauer B, Oberhuber G et al. Expression 16. Lu CW, Lin SC, Chen KF et al. Induction of pyruvate of hypoxia-inducible factor-1 alpha in oligodendro- dehydrogenase kinase-3 by hypoxia-inducible factor-1 gliomas: its impact on prognosis and on neoangiogene- promotes metabolic switch and drug resistance. J Biol 30. Plas DR, Thompson CB. Cell metabolism in the regula- 17. Kim JW, Tchernyshyov I, Semenza GL et al. HIF-1- tion of programmed cell death. Trends Endocrinol Me- mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to 31. Chen LB. Mitochondrial membrane potential in living hypoxia. Cell Metab 2006; 3 (3): 177-185. cells. Annu Rev Cell Biol 1988; 4: 155-181. 18. Koukourakis MI, Giatromanolaki A, Sivridis E et al. 32. Michelakis ED, Webster L, Mackey JR. Dichloroace- Lactate dehydrogenase-5 (LDH-5) overexpression in tate (DCA) as a potential metabolic-targeting therapy non-small-cell lung cancer tissues is linked to tumour for cancer. Br J Cancer 2008; 99 (7): 989-994. hypoxia, angiogenic factor production and poor prog- 33. Zamzami N, Kroemer G. The mitochondrion in apop- nosis. Br J Cancer 2003; 89 (5): 877-885. tosis: how Pandora's box opens. Nat Rev Mol Cell Biol 19. Koukourakis MI, Giatromanolaki A, Simopoulos C et al. Lactate dehydrogenase 5 (LDH5) relates to up- 34. Kim JW, Dang CV. Cancer's molecular sweet tooth and regulated hypoxia inducible factor pathway and metas- the Warburg effect. Cancer Res 2006; 66(18): 8927-30. tasis in colorectal cancer. Clin Exp Metastasis 2005; 35. Yeluri S, Madhok B, Prasad KR et al. Cancer's craving for sugar: an opportunity for clinical exploitation. J 20. Rajaganeshan R, Prasad R, Guillou PJ et al. Expression Cancer Res Clin Oncol 2009; 135 (7): 867-877. patterns of hypoxic markers at the invasive margin of 36. Madhok BM, Yeluri S, Perry SL et al. Targeting Glu- colorectal cancers and liver metastases. Eur J Surg On- cose Metabolism: An Emerging Concept for Anticancer 21. Rajaganeshan R, Prasad R, Guillou PJ et al. The role of 37. Shaw RJ. Glucose metabolism and cancer. Curr Opin hypoxia in recurrence following resection of Dukes' B colorectal cancer. Int J Colorectal Dis 2008; 23 (11): 38. Vander Heiden MG, Cantley LC, Thompson CB. Un- derstanding the Warburg effect: the metabolic require- Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) ments of cell proliferation. Science 2009; 324 (5930): 52. Rapisarda A, Hollingshead M, Uranchimeg B et al. Increased antitumor activity of bevacizumab in combi- 39. Thorn CC, Freeman TC, Scott N et al. Laser microdis- nation with hypoxia inducible factor-1 inhibition. Mol section expression profiling of marginal edges of colo- rectal tumours reveals evidence of increased lactate 53. Kummar S, Raffeld M, Juwara L et al. Multihistology, metabolism in the aggressive phenotype. Gut 2009; 58 target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1alpha in advanced solid 40. Kroemer G, Pouyssegur J. Tumor cell metabolism: tumors. Clin Cancer Res 2011; 17 (15): 5123-5131. cancer's Achilles' heel. Cancer Cell 2008; 13 (6): 472- 54. Zhang H, Qian DZ, Tan YS et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and 41. Pelicano H, Martin DS, Xu RH et al. Glycolysis inhibi- block tumor growth. Proc Natl Acad Sci U S A 2008; tion for anticancer treatment. Oncogene 2006; 25 (34): 55. Rowles J, Scherer SW, Xi T et al. Cloning and charac- 42. Scatena R, Bottoni P, Pontoglio A et al. Glycolytic terization of PDK4 on 7q21.3 encoding a fourth pyru- enzyme inhibitors in cancer treatment. Expert Opin In- vate dehydrogenase kinase isoenzyme in human. J Biol 43. De LM, Lorusso V, Latorre A et al. Paclitaxel, cisplatin 56. Gudi R, Bowker-Kinley MM, Kedishvili NY et al. Di- and lonidamine in advanced ovarian cancer. A phase II versity of the pyruvate dehydrogenase kinase gene fam- study. Eur J Cancer 2001; 37 (3): 364-368. ily in humans. J Biol Chem 1995; 270 (48): 28989- 44. Amadori D, Frassineti GL, De MA et al. Modulating effect of lonidamine on response to doxorubicin in me- 57. Popov KM, Kedishvili NY, Zhao Y et al. Molecular tastatic breast cancer patients: results from a multicen- cloning of the p45 subunit of pyruvate dehydrogenase ter prospective randomized trial. Breast Cancer Res kinase. J Biol Chem 1994; 269 (47): 29720-29724. 58. Bowker-Kinley MM, Davis WI, Wu P et al. Evidence 45. Pacini P, Rinaldini M, Algeri R et al. FEC (5- for existence of tissue-specific regulation of the mam- fluorouracil, epidoxorubicin and cyclophosphamide) malian pyruvate dehydrogenase complex. Biochem J versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced 59. Wu P, Sato J, Zhao Y et al. Starvation and diabetes breast cancer. A multicentric randomised study. Final increase the amount of pyruvate dehydrogenase kinase results. Eur J Cancer 2000; 36 (8): 966-975. isoenzyme 4 in rat heart. Biochem J 1998; 329 (Pt 1): 46. Berruti A, Bitossi R, Gorzegno G et al. Time to pro- gression in metastatic breast cancer patients treated 60. Pilegaard H, Neufer PD. Transcriptional regulation of with epirubicin is not improved by the addition of ei- pyruvate dehydrogenase kinase 4 in skeletal muscle ther cisplatin or lonidamine: final results of a phase III during and after exercise. Proc Nutr Soc 2004; 63(2): study with a factorial design. J Clin Oncol 2002; 20 61. Sugden MC, Holness MJ. Therapeutic potential of the 47. Papaldo P, Lopez M, Cortesi E et al. Addition of either mammalian pyruvate dehydrogenase kinases in the lonidamine or granulocyte colony-stimulating factor prevention of hyperglycaemia. Curr Drug Targets Im- does not improve survival in early breast cancer pa- mune Endocr Metabol Disord 2002; 2 (2): 151-165. tients treated with high-dose epirubicin and cyclophos- 62. Wigfield SM, Winter SC, Giatromanolaki A et al. phamide. J Clin Oncol 2003; 21 (18): 3462-3468. PDK-1 regulates lactate production in hypoxia and is 48. Kamlah F, Eul BG, Li S et al. Intravenous injection of associated with poor prognosis in head and neck siRNA directed against hypoxia-inducible factors pro- squamous cancer. Br J Cancer 2008; 98 (12): 1975- longs survival in a Lewis lung carcinoma cancer model. 63. Koukourakis MI, Giatromanolaki A, Sivridis E et al. 49. Stoeltzing O, McCarty MF, Wey JS et al. Role of hy- Pyruvate dehydrogenase and pyruvate dehydrogenase poxia-inducible factor 1alpha in gastric cancer cell kinase expression in non small cell lung cancer and tu- growth, angiogenesis, and vessel maturation. J Natl mor-associated stroma. Neoplasia 2005; 7 (1): 1-6. 64. Lu CW, Lin SC, Chien CW et al. Overexpression of 50. Kizaka-Kondoh S, Itasaka S, Zeng L et al. Selective pyruvate dehydrogenase kinase 3 increases drug resis- killing of hypoxia-inducible factor-1-active cells im- tance and early recurrence in colon cancer. Am J Pathol proves survival in a mouse model of invasive and me- tastatic pancreatic cancer. Clin Cancer Res 2009; 15 65. Koukourakis MI, Pitiakoudis M, Giatromanolaki A et al. Oxygen and glucose consumption in gastrointestinal 51. Rapisarda A, Zalek J, Hollingshead M et al. Schedule- adenocarcinomas: correlation with markers of hypoxia, dependent inhibition of hypoxia-inducible factor- acidity and anaerobic glycolysis. Cancer Sci 2006; 97 1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xeno- 66. McFate T, Mohyeldin A, Lu H et al. Pyruvate dehydro- grafts. Cancer Res 2004; 64 (19): 6845-6848. genase complex activity controls metabolic and malig- 2 Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism) nant phenotype in cancer cells. J Biol Chem 2008; 283 colorectal cancer. J Biomed Biotechnol 2011; 2011: 67. Bonnet S, Archer SL, lalunis-Turner J et al. A mito- 84. Fiebiger W, Olszewski U, Ulsperger E et al. In vitro chondria-K+ channel axis is suppressed in cancer and cytotoxicity of novel platinum-based drugs and di- its normalization promotes apoptosis and inhibits can- chloroacetate against lung carcinoid cell lines. Clin cer growth. Cancer Cell 2007; 11 (1): 37-51. 68. Stacpoole PW. Lactic acidosis. Endocrinol Metab Clin 85. Xie J, Wang BS, Yu DH et al. Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation 69. Stacpoole PW. Lactic acidosis and other mitochondrial and exhibits synergistic growth inhibition with cisplatin disorders. Metabolism 1997; 46 (3): 306-321. in HeLa cells. Int J Oncol 2011; 38 (2): 409-417. 70. Stacpoole PW, Lorenz AC, Thomas RG et al. Di- 86. Cao W, Yacoub S, Shiverick KT et al. Dichloroacetate chloroacetate in the treatment of lactic acidosis. Ann (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 71. Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Phar- 87. Khan A. Use of oral dichloroacetate for palliation of leg pain arising from metastatic poorly differentiated carci- 72. Stacpoole PW, Moore GW, Kornhauser DM. Metabolic noma: a case report. J Palliat Med 2011; 14 (8): 973-7. effects of dichloroacetate in patients with diabetes mel- 88. Flavin DF. Non-Hodgkin's Lymphoma Reversal with litus and hyperlipoproteinemia. N Engl J Med 1978; 73. Stacpoole PW. The pharmacology of dichloroacetate. Correspondence to:
74. Moore GW, Swift LL, Rabinowitz D et al. Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate. Athe- 75. Taniguchi M, Wilson C, Hunter CA et al. Dichloroace- tate improves cardiac efficiency after ischemia inde- pendent of changes in mitochondrial proton leak. Am J Physiol Heart Circ Physiol 2001; 280 (4): H1762-H1769. 76. Wambolt RB, Lopaschuk GD, Brownsey RW et al. Dichloroacetate improves postischemic function of hy-pertrophied rat hearts. J Am Coll Cardiol 2000; 36 (4): 1378-1385. 77. Platz TA, Wilson JS, Kline JA et al. The beneficial effects of dichloroacetate in acute limb ischemia. Mil Med 2007; 172 (6): 628-633. 78. Whitehouse S, Randle PJ. Activation of pyruvate dehy- drogenase in perfused rat heart by dichloroacetate (Short Communication). Biochem J 1973; 134 (2): 651-653. 79. Wong JY, Huggins GS, Debidda M et al. Dichloroace- tate induces apoptosis in endometrial cancer cells. Gy-necol Oncol 2008; 109 (3): 394-402. 80. Sun RC, Fadia M, Dahlstrom JE et al. Reversal of the glycolytic phenotype by dichloroacetate inhibits metas-tatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 2010; 120 (1): 253-260. 81. Vella S, Conti M, Tasso R et al. Dichloroacetate (DCA) inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. Int J Cancer 2011. 82. Madhok BM, Yeluri S, Perry SL et al. Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer 2010; 102 (12): 1746-1752. 83. Tong J, Xie G, He J et al. Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in Biomedical Research 2012 Volume 23 (Special Issue Cancer Metabolism)

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