Abstract
The metabolic phenotype of tumor cells promote the proliferative state, which indicates that (a) cell transformation is associated with the activation of specific metabolic substrate channels toward nucleic acid synthesis and (b) increased expression phosphorylation, allosteric or transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate unlimited growth. It is evident that cell transformation due to various K-ras point mutations is associated with the activation of specific metabolic substrate channels that increase glucose channeling toward nucleic acid synthesis. Therefore, phosphorylation, allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate cell transformation and growth. In this review, we summarize opposite changes in metabolic phenotypes induced by various cell-transforming agents, and tumor growth-inhibiting drugs or phytochemicals, or novel synthetic antileukemic drugs such as imatinib mesylate (Gleevec). Metabolic enzymes that further incite growth signaling pathways and thus promote malignant cell transformation serve as high-efficacy nongenetic novel targets for cancer therapies.
This article is to commemorate Dr. Boros, Ferenc János, a dedicated physician to his patients, a loving father and a memorable brother to the authors. Dr. Boros passed away of cancer in 2006 and this article is dedicated to his memory and to those who have suffered from this illness.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bares R, Klever P, Hauptmann S et al (1994) F-18 fluorodeoxyglucose PET in vivo evaluation of pancreatic glucose metabolism for detection of pancreatic cancer. Radiology 192:79–86
Boren J, Cascante M, Marin S et al (2001) Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J Biol Chem 276:37747–37753
Boros LG, Puigjaner J, Cascante M et al (1997) Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Res 57:4242–4248
Boros LG, Comin B, Boren J et al (2000a) Overexpression of transketolase: a mechanism by which thiamine supplementation promotes cancer growth (abstract). Proc Am Assoc Cancer Res 41:666
Boros LG, Lee W-NP, Hidvegi M et al (2000b) Metabolic effects of fermented wheat germ extract with anti-tumor properties in cultured MIA pancreatic adenocarcinoma cells. Pancreas 21:433
Boros LG, Torday JS, Lim S et al (2000c) Transforming growth factor beta2 promotes glucose carbon incorporation into nucleic acid ribose through the nonoxidative pentose cycle in lung epithelial carcinoma cells. Cancer Res 60:1183–1185
Boros LG, Bassilian S, Lim S et al (2001a) Genistein inhibits nonoxidative ribose synthesis in MIA pancreatic adenocarcinoma cells: a new mechanism of controlling tumor growth. Pancreas 22:1–7
Boros LG, Lapis K, Szende B et al (2001b) Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells. Pancreas 23:141–147
Chesney J, Mitchell R, Benigni F et al (1999) An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Proc Natl Acad Sci U S A 96:3047–3052
El-Zarruk AA, van den Berg HW (1999) The anti-proliferative effects of tyrosine kinase inhibitors towards tamoxifen-sensitive and tamoxifen-resistant human breast cancer cell lines in relation to the expression of epidermal growth factor receptors (EGF-R) and the inhibition of EGF-R tyrosine kinase. Cancer Lett 142:185–193
Hojo M, Morimoto T, Maluccio M et al (1999) Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397:530–534
Horecker BL (1965) Pathways of carbohydrate metabolism and their physiological significance. J Chem Educ 42:244–253
Horecker BL, Domagk G, Hiatt HH (1958) A comparison of C14-labeling patterns in deoxyribose and ribose in mammalian cells. Arch Biochem Biophys 78:510–517
Issa JP (2000) The epigenetics of colorectal cancer. Ann N Y Acad Sci 910:140–153
Jakab F, Mayer A, Hoffmann A et al (2000) First clinical data of a natural immunomodulator in colorectal cancer. Hepatogastroenterology 47:393–395
Jung I, Messing E (2000) Molecular mechanisms and pathways in bladder cancer development and progression. Cancer Control 7:325–334
Katz J, Rognstad R (1967) The labeling of pentose phosphate from glucose-14C and estimation of the rates of transaldolase, transketolase, the contribution of the pentose cycle and ribose phosphate synthesis. Biochemistry 6:2227–2247
Katz J, Lee W-NP, Wals PA et al (1989) Studies of glycogen synthesis and the Krebs cycle by mass isotopomer analysis with U-13C-glucose in rats. J Biol Chem 264:12994–13001
Kingsley-Hickman PB, Ross B, Krick T (1990) Hexose monophosphate shunt measurement in cultured cells with [1-13C]glucose: correction for endogenous carbon sources using [6-13C]Glucose. Anal Biochem 185:235–237
Krebs ET Jr, Krebs ET Sr, Beard HH (1950) The unitarian or trophoblastic thesis of cancer. Med Rec 163:150–171
Kunz-Schughart LA, Doetsch J, Mueller-Klieser W et al (2000) Proliferative activity and tumorigenic conversion: impact on cellular metabolism in 3-dimensional culture. Am J Physiol Cell Physiol 278:C765–C780
Largaespada DA (2000) Genetic heterogeneity in acute myeloid leukemia: maximizing information flow from MuLV mutagenesis studies. Leukemia 14:1174–1184
Lee WN, Bergner EA, Guo ZK (1992) Mass isotopomer pattern and precursor–product relationship. Biol Mass Spectrom 21:114–122
Lee W-NP (1993) Analysis of tricarboxylic acid cycle using mass isotopomer ratios. J Biol Chem 268:25522–25526
Lee W-NP, Byerley LO, Bassilian S et al (1995) Isotopomer study of lipogenesis in human hepatoma cells in culture: contribution of carbon and reducing hydrogen from glucose. Anal Biochem 226:100–112
Lian F, Bhuiyan M, Li YW et al (1998) Genistein-induced G2-M arrest, p21WAF1 upregulation and apoptosis in a non-small-cell lung cancer cell line. Nutr Cancer 31:184–191
Martin AM, Weber BL (2000) Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst 92:1126–1135
Oku T, Tjuvajev JG, Miyagawa T et al (1998) Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake and proliferation of human melanoma intracerebral xenografts. Cancer Res 58:4185–4192
Osthus RC, Shim H, Kim S et al (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275:21797–21800
Ozen M, Pathak S (2000) Genetic alterations in human prostate cancer: a review of current literature. Anticancer Res 20:1905–1912
Rais B, Comin B, Puigjaner J et al (1999) Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle. FEBS Lett 456:113–118
Raylman RR, Fisher SJ, Brown RS et al (1995) Fluorine-18-fluorodeoxyglucose-guided breast cancer surgery with a positron-sensitive probe: validation in preclinical studies. J Nucl Med 36:1869–1874
Sakai Y, Yanagisawa A, Shimada M et al (2000) K-ras gene mutations and loss of heterozygosity at the p53 gene locus relative to histological characteristics of mucin-producing tumors of the pancreas. Hum Pathol 31:795–803
Shim H, Chun YS, Lewis BC et al (1998) A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci U S A 95:1511–1516
Spitz DR, Sim JE, Ridnour LA et al (2000) Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann N Y Acad Sci 899:349–362
Strauss LG, Conti PS (1991) The application of PET in clinical oncology. J Nucl Med 32:623–648
Szabo C, Masiello A, Ryan JF et al (2000) The Breast Cancer Information Core: database design, structure and scope. Hum Mutat 16:123–131
Torizuka T, Tamaki N, Inokuma T et al (1995) In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET J Nucl Med 36:1811–1817
Waltron RT, Rozengurt E (2000) Oxidative stress induces protein kinase D activation in intact cell: involvement of Src and dependence on protein kinase C. J Biol Chem 275:17114–17121
Warburg O (1930) The metabolism of tumors. London, Costable
Warburg O (1956) On the origin of cancer cells. Science 123:309–314
Yatsuoka T, Sunamura M, Furukawa T et al (2000) Association of poor prognosis with loss of 12q, 17p and 18q and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma. Am J Gastroenterol 95:2080–2085
Zhou JR, Gugger ET, Tanaka T et al (1999) Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 129:1628–1635
Zwerschke W, Mazurek S, Massimi P et al (1999) Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc Natl Acad Sci U S A 96:1291–1296
Acknowledgements
This work was, in part, supported by the PHS M01-RR00425 of the General Clinical Research Unit, by NIH-AT00151, by P01-CA42710 of the UCLA Clinical Nutrition Research Unit Stable Isotope Core, its 009826-00-00 Preliminary Feasibility grant to LGB and by P01 AT003960-01 UCLA Center for Excellence in Pancreatic Diseases, Metabolomics Core, and a grant from the Hirshberg Foundation for Pancreatic Cancer Research.
Author information
Authors and Affiliations
Corresponding author
Editor information
Rights and permissions
Copyright information
© 2008 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Boros, L.G., Boros, T.F. (2008). Use of Metabolic Pathway Flux Information in Anticancer Drug Design. In: Kroemer, G., Mumberg, D., Keun, H., Riefke, B., Steger-Hartmann, ., Petersen, K. (eds) Oncogenes Meet Metabolism. Ernst Schering Foundation Symposium Proceedings, vol 2007/4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2008_094
Download citation
DOI: https://doi.org/10.1007/2789_2008_094
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-79477-6
Online ISBN: 978-3-540-79478-3
eBook Packages: MedicineMedicine (R0)