Azadeh Meshkin - Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

It is entirely accepted that a metabolic change in purine nucleotide concentration occursduring carcinogenesis which facilitate the pathological process of malignant cells such asproliferation, invasion and metastasis. Nucleotides participate in many biochemicalprocesses as activated precursors and source of energy in nucleic acid biosynthesis and asintermediate products for synthesis of lipids and proteins. However, currently it has beendocumented that purine nucleotides act as signaling molecules which directly or indirectlyregulate stability, subcellular localization and activation of plethora of proteins in cells.Although biosynthesis of purine nucleotides is up-regulated in malignant versus normal cells,the ratio of [ATP] and [GTP] is maintained constant about 7 to 1, which is critical for cellbiological process. This biological fact makes GTP as rate limiting factor not only in nucleicacid synthesis but also in regulation of survival and death signaling molecules whosefunctions are regulated by GTP content. In this line, several strategies were developed thatimpact on intracellular GTP content and disrupt the ratio of [ATP]/[GTP]. For instant, inhibitorshave been introduced in which some of them are in clinical trial at phase I and II, targetedinosine 5ˈ-monophosphate dehydrogenase (IMPDH) (type II) as rate limiting enzyme inGTP biosynthesis pathways in malignant cells. Mycophenolic acid, the most potent andselective IMPDH inhibitor, by depletion of intracellular GTP content disrupts purinenucleotides balance and conducts tumor cells toward apoptosis. On the other hands it hasbeen ascertained that extracellular purine nucleotides, themselves act as signalingmolecules which uptake by tumor cells through transporters on plasma membrane. In thatrespect, it has been disclosed that uptake of extracellular GTP by tumor cells leadingperturbation of intracellular purine nucleotides balance which impact on signaling moleculesand tilt cellʼs fate toward apoptosis. From therapeutic standpoint, modulation ofintracellular purine nucleotides by extracellular nucleotides or by selective inhibitors whichtarget rate limiting enzymes in nucleotides biosynthesis pathways could be considered as apotential therapeutic option for malignant cells.

Purine Nucleotides, Malignant Cells, Signaling Pathways, Apoptosis, Cancer Therapy