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.
Boros
L G
LG
Harbour-UCLA Medical Center RB1, Los Angeles Biomedical Research Institute, 1124 West Carson Street, Torrance, CA 90502, USA. lboros@sidmap.com
Boros
T F
TF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010641:Phenotype; D015398:Signal Transduction
D000970:Antineoplastic Agents