Use of Metabolic Pathway Flux Information in Anticancer Drug Design
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.
KeywordsMetabolic Phenotype Pyruvate Carboxylase Nucleic Acid Synthesis Glucose Carbon Increase Glucose Utilization
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.
- 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 41:666Google Scholar
- 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 21:433Google Scholar
- 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 142:185–193CrossRefPubMedGoogle Scholar
- Krebs ET Jr, Krebs ET Sr, Beard HH (1950) The unitarian or trophoblastic thesis of cancer. Med Rec 163:150–171Google Scholar
- 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 58:4185–4192PubMedGoogle Scholar
- Torizuka T, Tamaki N, Inokuma T et al (1995) In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET J Nucl Med 36:1811–1817Google Scholar
- Warburg O (1930) The metabolism of tumors. London, CostableGoogle Scholar